线粒体电子传递链组分COX5B与自噬途径协同调控MAVS介导的抗病毒天然免疫反应的分子机制

The innate immune response is the first line of defense against an invading pathogen.The mitochondrial outermembrane protein MAVS has been shown to play an essential role in the antiviral innate immune responses. However, the regulatory mechanisms of how MAVS is regulated at mitochondria remain elusive. Recently, our study has shown that the cytochrome c oxidase complex (CcO) subunit, COX5B, in the mitochondrial electron transport system acts in concert with the ATG5, a component of the autophagy pathway, to balance the MAVS-mediated antiviral signaling activity. To further understand the molecuar basis of COX5B/ATG5 complex in depth, in this proposal, we plan to integrate molecular biology, cell biology and biochemical approaches to pursue in-depth understanding of how COX5B regulate in the autophagy-mediated MAVS aggregation.Particularly, we try to elucidate the mechanism of how mitochondria and autophagy pathway work togather to balance the anti-virus signaling.This study will not only bring novel insights into understanding of innate immunity system acts against RNA virus, but also opens up a new avenue for clinical applications of new medicines by targeting to MAVS-mediated RLRs pathways.

天然免疫是机体防御外来病原物入侵的第一道防线。线粒体外膜蛋白MAVS是抗病毒天然免疫反应中的重要调控因子，但MAVS信号途径如何被调控的分子机制仍不清楚。我们最近研究表明线粒体电子传递链组分COX5B与自噬途径组分ATG5在平衡MAVS信号途径的活性起关键的作用。本项目主旨在于，在已有的研究工作基础上，试图运用生化和分子生物学相结合手段在分子水平上探讨电子传递链组分COX5B如何参与自噬途径调控线粒体外膜蛋白MAVS聚集体的解聚，以及自噬与MAVS功能的相互关系,从而探讨机体调控抗病毒天然免疫反应平衡的分子机理。这些研究将有助于我们对机体抗病毒的免疫分子机制的进一步理解，并为将来筛选以RLRs途径中MAVS为核心靶点的抗病毒药物的研究提供有力的理论依据。

天然免疫是机体防御外来病原物入侵的第一道防线。线粒体外膜蛋白MAVS是抗病毒天然免疫反应中的重要调控因子，但MAVS信号途径如何被调控的分子机制仍不清楚。我们最近研究表明线粒体电子传递链组分COX5B与自噬途径组分ATG5在平衡MAVS信号途径的活性起关键的作用。我们发现激活MAVS可以诱导自噬的产生，而且MAVS特异性介导了RLR信号通路诱导的自噬过程，敲除MAVS可以阻断RLR信号通路诱导的自噬。MAVS可以通过其LC3结合序列，YxxI，直接和LC3结合，这表明当RLR信号通路被过度激活后，MAVS可能作为自噬受体介导了线粒体的降解。我们的实验结果还显示，MAVS本身的寡聚化和招募的TRAF6/2蛋白都在MAVS介导的线粒体自噬过程中发挥着重要作用。总之，MAVS作为一个新发现的自噬受体，可以介导线粒体自噬过程，参与维持了线粒体的稳态，同时也调节了抗病毒天然免疫信号通路。这些研究将有助于我们对机体抗病毒的免疫分子机制的进一步理解，并为将来筛选以RLRs途径中MAVS为核心靶点的抗病毒药物的研究提供有力的理论依据。