cGAS与STING的去泛素化修饰及其调控抗病毒免疫与自身免疫的功能与机制研究

cGAS与STING在抗病毒免疫与自身免疫过程中起着关键的作用，其活性与稳态受到实时动态的泛素化调控。然而相关去泛素化调控机制及其在病毒免疫与自身免疫过程中的功能尚不清楚。我们前期的工作发现USP29与USP20分别去泛素化cGAS以及STING维持其蛋白水平的稳定性。敲除USP29或USP20促进病毒的复制，导致小鼠对HSV-1感染易感。在本项目中我们将通过一系列的分子生化实验阐明其机制。我们制备了Trex1敲除以及STING(N153S)的小鼠，拟将其与USP29或USP20敲除小鼠杂交获得双突变小鼠，分析自身免疫表型；同时筛选干预USP29或USP20功能的多肽或小分子，并结合分子生化与细胞实验研究其在调控病毒免疫与自身免疫性疾病中的功能与机制。本项目的成功完成，不仅对阐述病毒免疫与自身免疫的调控机制做出新的贡献，而且为未来治疗感染性与自身免疫性疾病提供分子靶标与先导药物。

cGAS and STING play critical roles in innate antiviral signaling and autoimmunity. It has been demonstrated that the function and activity of cGAS-STING signaling pathway are extensively regulated by (de)ubiquitination. Deubiquitination is mediated by deubiquitinating enzymes (DUBs) which are ideal druggble targets. However, the deubiquitination regulation of cGAS and STING is poorly understood. Our preliminary data suggest that USP29 and USP20 interact with and catalyze deubiquitination of cGAS and STING, respectively, which promotes the stability of cGAS and STING and antiviral immunity. Consistently, knockout of USP29 or USP20 in mice results in hyper-sensitivity to HSV-1 infection. We plan to investigate the mechanisms of USP29 and USP20-mediated regulation of cGAS and STING as well as the antiviral immune responses. On the other hand, cGAS and STING are important in autoimmunity and knockout of cGAS or STING rescues autoimmunity in mouse models including Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We have generated Trex1 knockout and STING(N153S) knockin mice, which are models for AGS, SLE, and STING-associated vasculopathy with onset in infancy (SAVI) diseases. In this project, we plan to cross Trex1 knockout and STING(N153S) knockin mice with USP29 or USP20 knockout mice to examine whether and how these DUBs are involved in regulation of autoimmunity. In addition, we will screen peptides or small molecules that interfere with USP29 or USP20 functions and investigate their roles in antiviral signaling and autoimmunity. We believe the results will not only advance our understanding of the regulation of antiviral signaling and autoimmunity, but also provide targets and lead compounds for infection- and autoimmunity-related diseases.