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https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Thomas+Dreo Proteopedia - User contributions [en] 2026-10-04T08:59:01Z User contributions MediaWiki 1.43.8 https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3360866 Sandbox Reserved 1647 2021-02-24T21:24:49Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='TBX21 on two DNA' scene='86/868180/Tbx21_on_dna/1' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a/2'>A</scene> / <scene name='86/868180/Chain_b/2'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA: The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302 <ref name="Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet">DOI 10.1073/pnas.0409512102</ref>. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/2o93 NFAT], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with GATA-3. <ref name="The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes">DOI 10.1073/pnas.0909357106</ref><br /> <br /> <br /> <br /> == Biological roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <ref name="NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression">DOI 10.4049/jimmunol.1203403</ref><br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <ref name="The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection">DOI 10.3389/fimmu.2019.00606</ref><br /> <br /> <br /> [[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]<br /> <br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of [[Mediator]] and [https://proteopedia.org/wiki/index.php/3mi9 P-TEFb] in the formation of the super elongation complex (SEC). Th1 genes are occupied by [[RNA Polymerase II]] in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to increased differentiation of Thp into Th1.<ref name="T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex">DOI 10.1016/j.celrep.2016.05.054</ref><br /> <br /> T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon ([https://proteopedia.org/wiki/index.php/6f1e IFN-γ]) transcription and by suppressing Th2-specific transcription factor [https://proteopedia.org/wiki/index.php/3dfx GATA-3]<ref name="A novel transcription factor, T-bet, directs Th1 lineage commitment">DOI 10.1016/s0092-8674(00)80702-3</ref>. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can take place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including [https://en.wikipedia.org/wiki/T_helper_17_cell Th17], [https://en.wikipedia.org/wiki/Regulatory_T_cell Treg], and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t [https://proteopedia.org/wiki/index.php/6b30 (ROR𝛾t)] <ref name="T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt">DOI 10.1038/ni.1969</ref>, runt-related transcription factor 3 [https://proteopedia.org/wiki/index.php/3mpm (RUNX3)], and B-cell lymphoma-6 [https://proteopedia.org/wiki/index.php/3lbz (BCL6)]. These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE antibodies]. T-bet was found associated with many immune-mediated diseases such as asthma.<ref name="Asthma: T-bet--a master controller?">DOI 10.1016/s0960-9822(02)00830-8</ref><br /> <br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines <ref name="The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells">DOI 10.1155/2014/589672</ref> that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on [https://en.wikipedia.org/wiki/USP10 USP10] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation. <ref name="Deubiquitination and stabilization of T-bet by USP10">DOI 10.1016/j.bbrc.2014.05.037</ref><br /> <br /> <br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3360865 Sandbox Reserved 1647 2021-02-24T21:11:05Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='TBX21 on two DNA' scene='86/868180/Tbx21_on_dna/1' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a/2'>A</scene> / <scene name='86/868180/Chain_b/2'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA: The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302 <ref name="Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet">DOI 10.1073/pnas.0409512102</ref>. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/2o93 NFAT], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Biological roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <ref name="NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression">DOI 10.4049/jimmunol.1203403</ref><br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]<br /> <br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of [[Mediator]] and [https://proteopedia.org/wiki/index.php/3mi9 P-TEFb] in the formation of the super elongation complex (SEC). Th1 genes are occupied by [[RNA Polymerase II]] in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to increased differentiation of Thp into Th1.<ref name="T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex">DOI 10.1016/j.celrep.2016.05.054</ref><br /> <br /> T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon ([https://proteopedia.org/wiki/index.php/6f1e IFN-γ]) transcription and by suppressing Th2-specific transcription factor [https://proteopedia.org/wiki/index.php/3dfx GATA-3]<ref name="A novel transcription factor, T-bet, directs Th1 lineage commitment">DOI 10.1016/s0092-8674(00)80702-3</ref>. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can take place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including [https://en.wikipedia.org/wiki/T_helper_17_cell Th17], [https://en.wikipedia.org/wiki/Regulatory_T_cell Treg], and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t [https://proteopedia.org/wiki/index.php/6b30 (ROR𝛾t)] <ref name="T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt">DOI 10.1038/ni.1969</ref>, runt-related transcription factor 3 [https://proteopedia.org/wiki/index.php/3mpm (RUNX3)], and B-cell lymphoma-6 [https://proteopedia.org/wiki/index.php/3lbz (BCL6)]. These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE antibodies]. T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines <ref name="The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells">DOI 10.1155/2014/589672</ref> that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on [https://en.wikipedia.org/wiki/USP10 USP10] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation. <ref name="Deubiquitination and stabilization of T-bet by USP10">DOI 10.1016/j.bbrc.2014.05.037</ref><br /> <br /> <br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3358317 Sandbox Reserved 1647 2021-02-22T12:13:26Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='TBX21 on two DNA' scene='86/868180/Tbx21_on_dna/1' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a/2'>A</scene> / <scene name='86/868180/Chain_b/2'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA: The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302 <ref name="Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet">DOI 10.1073/pnas.0409512102</ref>. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/2o93 NFAT], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Biological roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <ref name="NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression">DOI 10.4049/jimmunol.1203403</ref><br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]<br /> <br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of [[Mediator]] and [https://proteopedia.org/wiki/index.php/3mi9 P-TEFb] in the formation of the super elongation complex (SEC). Th1 genes are occupied by [[RNA Polymerase II]] in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon ([https://proteopedia.org/wiki/index.php/6f1e IFN-γ]) transcription and by suppressing Th2-specific transcription factor [https://proteopedia.org/wiki/index.php/3dfx GATA-3]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can take place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including [https://en.wikipedia.org/wiki/T_helper_17_cell Th17], [https://en.wikipedia.org/wiki/Regulatory_T_cell Treg], and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t [https://proteopedia.org/wiki/index.php/6b30 (ROR𝛾t)], runt-related transcription factor 3 [https://proteopedia.org/wiki/index.php/3mpm (RUNX3)], and B-cell lymphoma-6 [https://proteopedia.org/wiki/index.php/3lbz (BCL6)]. These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE antibodies]. T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines <ref name="The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells">DOI 10.1155/2014/589672</ref> that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on [https://en.wikipedia.org/wiki/USP10 USP10] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3346628 Sandbox Reserved 1647 2021-01-23T17:02:51Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='TBX21 on two DNA' scene='Tbx21_on_dna' /><br /> ==Introduction==<br /> <scene name='86/868180/Tbx21_on_dna/1'>TBX21</scene> or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a/2'>A</scene> / <scene name='86/868180/Chain_b/2'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA: The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene> and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/2o93 NFAT], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]<br /> <br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of [[Mediator]] and [https://proteopedia.org/wiki/index.php/3mi9 P-TEFb] in the formation of the super elongation complex (SEC). Th1 genes are occupied by [[RNA Polymerase II]] in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon ([https://proteopedia.org/wiki/index.php/6f1e IFN-γ]) transcription and by suppressing Th2-specific transcription factor [https://proteopedia.org/wiki/index.php/3dfx GATA-3]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can take place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including [https://en.wikipedia.org/wiki/T_helper_17_cell Th17], [https://en.wikipedia.org/wiki/Regulatory_T_cell Treg], and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t [https://proteopedia.org/wiki/index.php/6b30 (ROR𝛾t)], runt-related transcription factor 3 [https://proteopedia.org/wiki/index.php/3mpm (RUNX3)], and B-cell lymphoma-6 [https://proteopedia.org/wiki/index.php/3lbz (BCL6)]. These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE antibodies]. T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on [https://en.wikipedia.org/wiki/USP10 USP10] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3346489 Sandbox Reserved 1647 2021-01-20T09:18:20Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT[[https://proteopedia.org/wiki/index.php/2o93]], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1[[https://proteopedia.org/wiki/index.php/1co1]], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65[[https://proteopedia.org/wiki/index.php/2i9t]] and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator[[https://proteopedia.org/wiki/index.php/Mediator]] and P-TEFb[[https://proteopedia.org/wiki/index.php/3mi9]] in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II[[https://proteopedia.org/wiki/index.php/RNA_Polymerase_II]] in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[https://proteopedia.org/wiki/index.php/6f1e]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17[[https://proteopedia.org/wiki/index.php/6ucg]], Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies[[https://proteopedia.org/wiki/index.php/2r56]].T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10[[https://proteopedia.org/wiki/index.php/2lbc]] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3346405 Sandbox Reserved 1647 2021-01-20T09:05:09Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT[[https://proteopedia.org/wiki/index.php/2o93]], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1[[https://proteopedia.org/wiki/index.php/1co1]], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65[[https://proteopedia.org/wiki/index.php/2i9t]] and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator[[https://proteopedia.org/wiki/index.php/Mediator]] and P-TEFb[[https://proteopedia.org/wiki/index.php/3mi9]] in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II[[https://proteopedia.org/wiki/index.php/RNA_Polymerase_II]] in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[https://proteopedia.org/wiki/index.php/6f1e]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies[[https://proteopedia.org/wiki/index.php/2r56]].T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10[[https://proteopedia.org/wiki/index.php/2lbc]] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3345927 Sandbox Reserved 1647 2021-01-20T08:50:31Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT[[https://proteopedia.org/wiki/index.php/2o93]], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1[[https://proteopedia.org/wiki/index.php/1co1]], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65[[https://proteopedia.org/wiki/index.php/2i9t]] and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[https://proteopedia.org/wiki/index.php/3mi9]] and mediator [[https://proteopedia.org/wiki/index.php/Mediator]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[https://proteopedia.org/wiki/index.php/6f1e]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies[[https://proteopedia.org/wiki/index.php/2r56]].T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10[[https://proteopedia.org/wiki/index.php/2lbc]] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> 1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102<br /> <br /> 2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet<br /> Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang<br /> The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403<br /> <br /> 3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672<br /> <br /> 4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037<br /> <br /> 5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606<br /> <br /> 6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054<br /> <br /> 7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731<br /> <br /> 8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969<br /> <br /> 9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3<br /> <br /> 10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8<br /> <br /> 11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106</div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3345447 Sandbox Reserved 1647 2021-01-20T08:24:18Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT[[https://proteopedia.org/wiki/index.php/2o93]], the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1[[https://proteopedia.org/wiki/index.php/1co1]], the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65[[https://proteopedia.org/wiki/index.php/2i9t]] and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[https://proteopedia.org/wiki/index.php/3mi9]] and mediator [[https://proteopedia.org/wiki/index.php/Mediator]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[https://proteopedia.org/wiki/index.php/6f1e]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies[[https://proteopedia.org/wiki/index.php/2r56]].T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10[[https://proteopedia.org/wiki/index.php/2lbc]] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3344823 Sandbox Reserved 1647 2021-01-20T08:06:09Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT, the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1, the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65 and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[https://proteopedia.org/wiki/index.php/3mi9]] and mediator [[https://proteopedia.org/wiki/index.php/Mediator]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[https://proteopedia.org/wiki/index.php/6f1e]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies.T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE[[https://proteopedia.org/wiki/index.php/2r56]]. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10[[https://proteopedia.org/wiki/index.php/2lbc]] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3344821 Sandbox Reserved 1647 2021-01-20T08:01:16Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT, the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1, the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65 and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[https://proteopedia.org/wiki/index.php/3mi9]] and mediator [[https://proteopedia.org/wiki/index.php/Mediator]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[https://proteopedia.org/wiki/index.php/6f1e]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies.T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE[[https://proteopedia.org/wiki/index.php/2r56]]. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10 is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3342476 Sandbox Reserved 1647 2021-01-15T17:08:12Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT, the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1, the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65 and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[https://proteopedia.org/wiki/index.php/3mi9]] and mediator [[https://proteopedia.org/wiki/index.php/Mediator]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies.T-bet was found associated with many immune-mediated diseases such as asthma.<br /> <br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> <br /> In T-bet structure, ubiquitination takes place at <scene name='86/868180/Lys313/1'>LYS 313</scene>. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10 is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.<br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3342433 Sandbox Reserved 1647 2021-01-15T11:02:56Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to <scene name='86/868180/Link_to_2_dna/1'>link two DNA molecules with only one dimer</scene>. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of <scene name='86/868180/Helix_and_strand/1'>β-strands and α-helix</scene> and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT, the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1, the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65 and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[https://proteopedia.org/wiki/index.php/3mi9]] and mediator [[https://proteopedia.org/wiki/index.php/Mediator]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ) transcription and by suppressing Th2-specific transcription factor GATA-3 [[https://proteopedia.org/wiki/index.php/3dfx]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[https://proteopedia.org/wiki/index.php/6b30]], runt-related transcription factor 3 (RUNX3)[[https://proteopedia.org/wiki/index.php/3mpm]], and B-cell lymphoma-6 (BCL6)[[https://proteopedia.org/wiki/index.php/3lbz]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies. T-bet was found associated with many immune-mediated diseases such as asthma and systemic sclerosis for example.<br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> In T-bet structure, ubiquitination takes place at Lysine 313. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10 is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3342381 Sandbox Reserved 1647 2021-01-14T20:22:21Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to link two DNA molecules with only one dimer. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of β-strands and α-helices and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT, the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1, the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65 and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ) transcription and by suppressing Th2-specific transcription factor GATA-3. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t), runt-related transcription factor 3 (RUNX3), and B-cell lymphoma-6 (BCL6).These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> === TBX21 as an antiasthmatic regulator ===<br /> Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies. T-bet was found associated with many immune-mediated diseases such as asthma and systemic sclerosis for example.<br /> In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.<br /> In T-bet structure, ubiquitination takes place at Lysine 313. It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10 is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.<br /> <br /> <br /> == Structural highlights ==<br /> <br /> This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3342268 Sandbox Reserved 1647 2021-01-14T18:22:45Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to link two DNA molecules with only one dimer. Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop.<br /> The main function of this transcription factor is to direct [https://en.wikipedia.org/wiki/T_helper_cell TH1 cells differentiation] from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.<br /> <br /> == Structure and structural interactions ==<br /> ===Primary Structure===<br /> <br /> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]<br /> The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/1'>LYS 135</scene> and <scene name='86/868180/Asn_326/1'>ASN 326</scene>. <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of β-strands and α-helices and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of <scene name='86/868180/Lys314/1'>K 313</scene> is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue <scene name='86/868180/Lys314/1'>K 313</scene> allows TBX21 to bind with the DNA sequence. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of <scene name='86/868180/Thr302/1'>T 302</scene> allows TBX21 to interact with NFAT, the one of <scene name='86/868180/Tyr304/1'>Y 304</scene> allows TBX21 to interact with RUNX1, the one of <scene name='86/868180/Ser508/1'>S 508</scene> allows the interaction with NF-кB p65 and finaly the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ) transcription and by suppressing Th2-specific transcription factor GATA-3. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues <scene name='86/868180/Tyr219/1'>TYR 219</scene>, <scene name='86/868180/Tyr265/1'>TYR 265</scene>, and <scene name='86/868180/Tyr304/1'>TYR 304</scene>. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t), runt-related transcription factor 3 (RUNX3), and B-cell lymphoma-6 (BCL6).These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> <br /> <br /> == Structural highlights ==<br /> <br /> This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=Sandbox_Reserved_1647&diff=3342159 Sandbox Reserved 1647 2021-01-14T15:13:23Z

<p>Thomas Dreo: </p> <hr /> <div><Structure load='5t1j' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br /> ==Introduction==<br /> TBX21 or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. The DNA binding domain of T-bet has a dimer structure composes of two identical chains (<scene name='86/868180/Chain_a_bis/1'>A</scene> / <scene name='86/868180/Chain_b/1'>B</scene> ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to link two DNA molecules or two areas of the same DNA molecules which are far from each other.<br /> <br /> == Structure and structural interactions ==<br /> <br /> === Secondary structure and interactions ===<br /> <br /> The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of β-strands and α-helices and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of K313 is associated with the phosphate of a DNA base via hydrogen-bond interaction.<br /> Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue K313 allows TBX21 to bind with the DNA sequence. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of T302 allows TBX21 to interact with NFAT, the one of Y304 allows TBX21 to interact with RUNX1, the one of S508 allows the interaction with NF-кB p65 and finally the one of Y525 allows the interaction with GATA-3.<br /> <br /> <br /> == Some roles of TBX21 ==<br /> === Regulation of Th cells differentiation by TBX21 ===<br /> The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. <br /> We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production. <br /> [[Image:TBET.jpg]]<br /> <br /> Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb and mediator and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.<br /> <br /> T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ) transcription and by suppressing Th2-specific transcription factor GATA-3. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.<br /> This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues 219, 265, and 304. C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.<br /> <br /> Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t), runt-related transcription factor 3 (RUNX3), and B-cell lymphoma-6 (BCL6).These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.<br /> <br /> <br /> <br /> == Structural highlights ==<br /> <br /> This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Thomas Dreo https://proteopedia.org/index.php?title=File:TBET.jpg&diff=3342156 File:TBET.jpg 2021-01-14T15:08:33Z

<p>Thomas Dreo: Interaction of T-Bet in the recruitment of P-TEFb and mediator.</p> <hr /> <div>== Summary ==<br /> Interaction of T-Bet in the recruitment of P-TEFb and mediator.<br /> == Licensing ==<br /> {{self|cc-by-3.0}}</div>

Thomas Dreo