Sandbox Reserved 1647: Difference between revisions

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>.

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>.

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>.

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>.

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 <ref>PMID: 512268</ref>.