FOXP3蛋白泛素化与去泛素化修饰调控Treg细胞功能的机理研究

Protein ubiquitination modification plays a critical role in the immune cell lineage differentiation and function. In Regualtory T cells, protein ubiquitination participates in the regulation of cell development,signal transduction and physiological function. Forkhead family transcription factor FOXP3 is the most critical factor for Treg development and funciton. Our preliminary work revealed FOXP3 specific ubiquitinase Stub1 and deubiquitinase USP44, and their effect on FOXP3 function by the modification. On the basis of our previous study, we will further analyse the mechanism underlying how ubiquitination and deubiquitination affects FOXP3 stability and activity, as well as how the modifications are involved in Treg cell function and related immune disease control. This in-depth and systematic work will help us to fill the gap in the FOXP3 post-translatinal modification, extend our cognition on mechanism in Treg cell manipulation, and shed light on the new molecular mechanism underlying the critical role of Treg cells in the immune system. This study will lay a basis on the better understanding of FOXP3 mediated transcription regulation and provide new clues for the treatment of important human diseases.

免疫系统中决定不同亚型细胞分化与功能的关键性转录调控蛋白的泛素化修饰决定其蛋白稳定性及转录活性。蛋白泛素化修饰对FOXP3+调节性T细胞(Treg)的分化发育、信号传导及生理功能皆有非常重要的调节作用。叉头状蛋白家族转录因子FOXP3是决定Treg分化及生理功能的最关键性转录因子。我们前期工作发现了直接作用于FOXP3蛋白的泛素化酶Stub1和去泛素化酶USP44。在此研究基础上，我们将进一步深入系统地分析不同生理及病理微环境下FOXP3蛋白泛素化及去泛素化修饰如何动态影响FOXP3+Treg的生理功能。本研究的深入开展将发现新的FOXP3蛋白翻译后修饰的酶学调控机制，为进一步理解FOXP3转录活性调节机制的正负调控提供坚实基础，从而为人类重大免疫相关疾病的临床治疗提供原创性新靶点和新线索。

我们前期工作发现了直接作用于FOXP3 蛋白的泛素化酶Stub1 和去泛素化酶USP44。在此研究基础上，我们发现去泛素化酶USP21阻止FOXP3蛋白的降解并抑制Th1-like Treg细胞的产生。Treg细胞中特异性敲除Usp21基因的小鼠自发过度激活的T细胞免疫反应，并诱导产生Th1-like Treg细胞。去泛素化酶USP21能去泛素化并稳定FOXP3蛋白，进而维持Treg细胞标志性基因的表达。因此，我们证明去泛素化酶USP21能阻止FOXP3蛋白降解，进而在体内调控Treg细胞的稳定性。因此，本研究的深入开展将发现新的FOXP3 蛋白翻译后修饰的酶学调控机制，为进一步理解FOXP3 转录活性调节机制的正负调控提供坚实基础，从而为人类重大免疫相关疾病的临床治疗提供原创性新靶点和新线索。