Regulation of T cell homeostasis and activation by MALT1-TRAF6 interaction (A04)

MALT1的蛋白水解酶活性裂解信号介体、转录调节因子和核糖核酸结合蛋白以增强T细胞的激活，而MALT1招募泛素连接酶TRAF6来激活典型的NF-B信号。我们建立了MALT1的两个TRAF6结合位点(T6BM1和T6BM2)具有破坏性突变的Malt1TBM/TBM小鼠，这两个位点表现出T细胞驱动的自身免疫和自身炎症。在这个项目中，我们将阐明TRAF6如何在常规和调节T细胞亚群中平衡MALT1支架和蛋白酶功能。耐人寻味的是，人类T6BM2纯合子胚系突变导致了一种复杂的免疫紊乱，患者出现免疫缺陷和自身免疫的迹象。因此，我们将表征这些不同突变对MALT1-TRAF6相互作用的调节如何调节小鼠的T细胞激活和免疫稳态。与之前关于TRAF6是炎症驱动因素的假设相反，我们的研究将揭开序幕，如果TRAF6失活突变和抑制实际上可能通过释放MALT1蛋白酶而导致自身免疫和炎症。

The MALT1 protease activity cleaves signaling mediators, transcriptional regulators and RNA-binding proteins to augment T cell activation, and MALT1 recruits the ubiquitin ligase TRAF6 to activate canonical NF-B signaling. We generated Malt1TBM/TBM mice with destructive mutations in the two TRAF6 binding sites (T6BM1 and T6BM2) of MALT1, which exhibit T cell-driven autoimmunity and autoinflammation. Within this project, we will elucidate how TRAF6 balances MALT1 scaffolding and protease functions in conventional and regulatory T cell subsets. Intriguingly, a human homozygous germline mutation in the T6BM2 leads to a complex immune disorder with signs of immune deficiency and autoimmunity in the affected patient. Thus, we will characterize how tuning of MALT1-TRAF6 interactions by these different mutations modulate T cell activation and immune homeostasis in mice. Contrary to previous assumptions on TRAF6 as a driver of inflammation, our studies will unravel, if TRAF6 inactivating mutations and inhibition may in fact cause autoimmunity and inflammation by unleashing the MALT1 protease.