Proteopedia - User contributions [en]

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2022-01-13T15:03:04Z

Alexia Karl:

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2022-01-13T14:40:40Z

Alexia Karl:

<scene name='86/868180/Tbx21/3'>Text To Be Displayed</scene><StructureSection load='TBX21.pdb' size='340' side='right' caption='T-Box transcription factor 21 (TBX21)' scene=''>

==Introduction==
<scene name='86/868180/Tbx21/3'>TBX21</scene> (for t-box transcription factor 21) or T-bet is a [https://en.wikipedia.org/wiki/Transcription_factor transcription factor], more precisely a [[T-box proteins]]. These transcription factors are known to be specialised in the regulation of developmental processes, especially with immune cells. The DNA binding domain of T-bet has a dimer structure composed 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 the protein to bind itself on the DNA promotor or regulator area. T-box protein is able to <scene name='86/868180/Tbx21_on_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. 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. T-bet is interact with <scene name='86/868180/Stat4/1'>the amino-terminal protein domain of Stat4</scene> (signal transducer and activator of transcription 4) for Th1 gene expression <ref name="">TBX21/T-Bet polyclonal antibody : https://www.thermofisher.com/antibody/product/TBX21-T-bet-Antibody-Polyclonal/13700-1-AP</ref>. Nevertheless, the action field of T-bet is larger than classical T-box protein.

==Location==

TBX21 protein is coded by the [https://en.wikipedia.org/wiki/TBX21 TBX21] gene on the chromosome 17 in humans. More precisely on the band 17q21.32. <ref name="TBX21 Gene - GeneCards">TBX21-GeneCards : TBX21 - T-box Transcription factor 21 :https://www.genecards.org/cgi-bin/carddisp.pl?gene=TBX21</ref>

== Structure and structural interactions ==
===Primary Structure===

The DNA binding domain of T-bet from ''Mus musculus'' for a monomer is located between the residues <scene name='86/868180/Lys135/2'>LYS 135</scene> and <scene name='86/868180/Asn_326/4'>ASN 326</scene> [[Image:ImageProteopedia.PNG|thumb |left|upright=3 |Figure of primary structure of T-bet protein from ''Mus musculus'']]

=== Secondary structure and interactions ===

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.
Thanks to some [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] of the protein’s residues, the transcription factor TBX21 can bind with DNA between the residues <scene name='86/868180/Lys135/2'>LYS 135</scene> and <scene name='86/868180/Asn_326/4'>ASN 326</scene> and some proteins. Firstly, the ubiquitination of the residue K 313 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 [https://proteopedia.org/wiki/index.php/6f1e 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. For example, phosphorylation of T 302 allows TBX21 to interact with [https://proteopedia.org/wiki/index.php/2o93 NFAT], the one of Y 304 with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], that of S 508 with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with <scene name='86/868180/Dna_binding_by_gata_transcript/2'>GATA-3</scene><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>

== Biological roles of TBX21 ==
=== Regulation of Th cells differentiation by TBX21 ===
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 on the action's mechanism 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>
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>

[[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]

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. The recruitment of P-TEFb and mediator activates transcriptional elongation and 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>

T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon (IFN-γ) transcription <ref name="The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation.">DOI 10.1038/ni.1731</ref>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"> 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</ref>. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells.
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 TYR 219, TYR 265, and TYR 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.

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.

=== TBX21 as an antiasthmatic regulator ===
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?">Douglas.S.Robinson and Clare M Lloyd. Asthma: T-bet - A master controller ? Volume 12, Issue 9, PR322-R324, April 30, (2002) https://doi.org/10.1016/S0960-9822(02)00830-8</ref>

Th1, Th2 and Th17 cells are the main cells involved in the pathophysiology of asthma <ref name="Effect of ginger extract on expression of GATA3, T-bet and ROR-γt in peripheral blood mononuclear cells of patients with Allergic Asthma">DOI 10.1016/j.aller.2018.12.003</ref>. 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, which can be the cause of severe forms of asthma. 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.<ref name="Asthma: T-bet--a master controller?">DOI 10.1016/s0960-9822(02)00830-8</ref> Also, some research has found that airway reactivity is moderated by the use of corticosteroids in asthma patients and with the use of it the TBX21 variant increases Th1 and decreases Th2 cytokine expression. So TBX21 may be determinant in the therapy of asthma with inhaled corticosteroids. <ref name="TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids">DOI 10.1073/pnas.0408532102</ref>

In T-bet structure, ubiquitination takes place at LYS 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 [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 of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.

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>

Over the past few years, it has been shown by researchers that the polymorphism of TBX21 could act on nasal polyps and aspirin intolerance too. Patients that cumulate aspirin-intolerance and asthma suffer from bronchoconstriction when using aspririn. This bronchoconstriction is due to the production of cysteinyl leukotrienes, a family of inflammatory mediators, triggered by aspirin intake.
</StructureSection>
== References ==
<references/>

2021-12-28T19:48:01Z

Alexia Karl:

<Structure load='5t1j' size='350' frame='true' align='right' caption='TBX21 on two DNA' scene='86/868180/Tbx21_on_dna/1' />
==Introduction==
TBX21 (for t-box transcription factor 21) 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 the protein to bind itself on the DNA promotor or regulator area. T-box protein 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.
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.

==Location==

TBX21 protein is coded by the [https://en.wikipedia.org/wiki/TBX21 TBX21] gene on the chromosome 17 in humans. More precisely on the band 17q21.32.

== Structure and structural interactions ==
===Primary Structure===

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> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]

=== Secondary structure and interactions ===

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.
Thanks to some [https://en.wikipedia.org/wiki/Post-translational_modification 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 [https://proteopedia.org/wiki/index.php/6f1e 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. For example, 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> with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], that of <scene name='86/868180/Ser508/1'>S 508</scene> with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with <scene name='86/868180/Dna_binding_by_gata_transcript/2'>GATA-3</scene><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>

== Biological roles of TBX21 ==
=== Regulation of Th cells differentiation by TBX21 ===
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 on the action's mechanism 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>
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>

[[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]

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. The recruitment of P-TEFb and mediator activates transcriptional elongation and 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>

T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon (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.
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.

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.

=== TBX21 as an antiasthmatic regulator ===
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>

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.<ref name="Asthma: T-bet--a master controller?">DOI 10.1016/s0960-9822(02)00830-8</ref>

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.

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>

== References ==
<references/>
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

2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet
Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang
The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403

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

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

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

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

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

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

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

10 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

Sandbox Reserved 1647

2021-12-28T19:47:03Z

Alexia Karl:

<Structure load='5t1j' size='350' frame='true' align='right' caption='TBX21 on two DNA' scene='86/868180/Tbx21_on_dna/1' />
==Introduction==
TBX21 (for t-box transcription factor 21) 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 the protein to bind itself on the DNA promotor or regulator area. T-box protein 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.
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.

==Location==

TBX21 protein is coded by the [https://en.wikipedia.org/wiki/TBX21 TBX21] gene on the chromosome 17 in humans. More precisely on the band 17q21.32.

== Structure and structural interactions ==
===Primary Structure===

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> [[Image:T-Bet primary structure.PNG|thumb |left|upright=3 |schema of primary structure of T-bet protein from ''Mus musculus'']]

<Structure load='GATA-3.pdb' size='350' frame='true' align='right' caption='DNA binding by GATA transcription factor-complex 3' scene='Insert optional scene name here' />

=== Secondary structure and interactions ===

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.
Thanks to some [https://en.wikipedia.org/wiki/Post-translational_modification 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 [https://proteopedia.org/wiki/index.php/6f1e 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. For example, 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> with [https://proteopedia.org/wiki/index.php/1co1 RUNX1], that of <scene name='86/868180/Ser508/1'>S 508</scene> with [https://proteopedia.org/wiki/index.php/2i9t NF-кB p65] and finally the one of Y525 allows the interaction with GATA-3. <scene name='86/868180/Dna_binding_by_gata_transcript/2'>GATA-3</scene><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>

== Biological roles of TBX21 ==
=== Regulation of Th cells differentiation by TBX21 ===
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 on the action's mechanism 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>
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>

[[Image:TBET.jpg|thumb|upright=2 |T-bet action in the formation of SEC]]

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. The recruitment of P-TEFb and mediator activates transcriptional elongation and 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>

T-bet can also regulate Th1 cell differentiation by directly initiating gamma interferon (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.
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.

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.

=== TBX21 as an antiasthmatic regulator ===
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>

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.<ref name="Asthma: T-bet--a master controller?">DOI 10.1016/s0960-9822(02)00830-8</ref>

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.

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>

== References ==
<references/>
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

2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet
Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang
The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403

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

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

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

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

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

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

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

10 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