RIG-I-MAVS介导的抗病毒天然免疫信号通路的调节机制

RIG-I plays an essential role in sensing virus-related double stranded RNA (dsRNA) and activating downstream signal transduction pathway for the production of interferonβ. After binding to dsRNA harboring 5'-triphosphate, RIG-I is activated and undergoes a conformational change, which together with free K63-linked ubiquitin chains activates MAVS, an adaptor protein on the outer membrane of mitohcondria. It was found recently that upon viral infection MAVS forms aggregates to activate downstream signaling pathway and MAVS aggregation is both necessary and sufficient for its function. Most importantly, MAVS aggregation goes through a prion-like conformational change. However, how RIG-I-MAVS signaling is regulated in cells is largely unknown. We propose to study how MAVS aggregates are cleared in cells after an immune response is called off to minimize the detrimental effect from excessive inflammation. In addition, as Atg12-Atg5, an autohpage component, was reported to inhibit RIG-I-MAVS signaling, we will study the molecular mechanism underlying the inhibition and gain insight into physiological relevance, i.e. how RIG-I-MAVS signaling is regulated by autophagy in cells. Our studies will not only advance our knowledge in antiviral innate immune signaling but also provide valuable basis for antiviral medicine in pharmaceutical and clinical application.

RIG-I是细胞内感知病毒侵染并引发天然免疫反应的受体之一。RIG-I的激活需要与病毒相关的RNA分子（具有5'端三磷酸、双链等结构特征）和K63-连接的泛素链。RIG-I随后激活接头分子MAVS和下游的信号通路，直至产生干扰素以抑制病毒的复制与扩增。最近的研究表明在病毒侵染宿主细胞以后，RIG-I促使MAVS形成巨大的多聚体，MAVS多聚体能够激活下游的信号通路。但是，MAVS多聚体在细胞内是怎样被调节的还未有报道。本项目计划在分子水平上研究MAVS多聚体在细胞内是怎样被消除的，因为这是在病毒感染被抑制以后避免过度炎症反应的重要一环。同时探索MAVS形成多聚体的过程是怎样被autophage调节的，还将具体研究Atg12-Atg5是怎样抑制MAVS多聚体的形成。以上研究将阐明抗病毒天然免疫反应的分子机制，并将为相关的药物研究提供理论基础。

RIG-I会识别侵染细胞的病毒核糖核酸分子(RNA)，并激活其下游的接头蛋白分子MAVS。被激活的MAVS分子会进一步形成朊蛋白样(prion-like)的聚集结构并激活下游特定的信号通路以诱导I型干扰素的表达，从而抑制病毒的复制和扩散。但是关于MAVS分子自我调控机制的相关研究仍很不清楚。在本项目的结题报告中，我们发现并鉴定了MAVS分子内部负责激活下游信号通路的关键氨基酸基序，这些关键的功能区段通过招募不同的TRAF分子，特异性的激活转录因子NF-κB和IRF3。同时，我们发现这些氨基酸基序在静息状态下被其相邻的氨基酸区段所自我抑制，从而防止MAVS在细胞内非特异性的诱导I型干扰素相关基因的表达。综上，我们的研究建立了一个全新的静息状态下MAVS自我调控的模型，揭示了细胞在非感染状态下维持自我稳态的新机制，为控制过度炎症以及一些自身免疫性疾病的治疗提供了新的思路。