RIG-I样受体（RLRs，包括RIG-I、MDA5、LGP2）是细胞抵御病毒入侵的模式识别受体。当RIG-I和MDA5与病毒RNA结合时发生构象改变并与线粒体外膜上的MAVS蛋白结合进而激发固有免疫反应。这一过程依赖于宿主细胞E3泛素连接酶TRIM25介导的RIG-I和/或MAVS分子寡泛素化，但目前对于TRIM25如何与RIG-I或MAVS相互作用并产生共价或非共价结合的寡泛素链仍不清楚。本项目将对这一悬而未决的重要科学问题进行探索，通过生物物理学方法研究TRIM25与RIG-I及MAVS间可能存在的相互作用和复合物结构。另一方面，不同病毒发展进化出多种针对RLR-MAVS信号通路的逃避机制。我们将研究甲型流感病毒NS1蛋白拮抗RIG-I和TRIM25等宿主蛋白的具体机制和结构基础，并通过基于片段的NMR筛选新方法寻找抑制NS1蛋白的小分子，作为研发抗病毒创新药物的第一步。

RIG-I-like receptors (RLRs, including RIG-I, MDA5, and LGP2) are pattern recognition receptors that sense viral RNA and trigger innate immunity responses. Upon activation by viral RNA, RIG-I and MDA5 undergo conformational change and interact with the mitochondrial bound protein MAVS (IPS-1/VISA/Cardif）to induce signalling. Ubiquitination of RIG-I and/or MAVS, mediated by the E3 ubiquitin ligase TRIM25, is crucial to this process. However, molecular mechanism for the TRIM25-RIG-I/MAVS interactions and the generation of coupled or uncoupled K63-ubiquitin chains remains elusive. This project aims to investigate the molecular interactions among TRIM25, RIG-I and MAVS. Moreover, viruses developed various strategies to overcome the host RLR-MAVS system. We will investigate how the NS1 protein of influenza A virus antagonize RIG-I and TRIM25, and will develop small molecule inhibitors targeting NS1 protein through fragment-based NMR screening.