天然免疫系统是机体抵抗病原微生物入侵的第一道防线，它首先通过模式识别受体(PRRs)与病原体相关分子模式(PAMPs)相互识别，进一步激活一系列的免疫反应。同时，宿主细胞通过多种方式负调节天然免疫反应的信号通路，以保证信号传导的平衡，进而防止过度免疫反应对宿主细胞造成损伤。在抗RNA病毒天然免疫中，主要有两类PRRs: TLRs和RLRs。MAVS作为RLRs介导的抗病毒免疫信号通路中的重要接头蛋白，通过C端的TM结构域定位于线粒体外膜，它的线粒体定位对于其功能的发挥至关重要。尽管以往对于MAVS的分子调控机制进行了较多的研究，但是人们对MAVS定位于线粒体外膜的功能还很不清楚。
中科院动物研究所孙钦秒研究组通过酵母双杂筛选得到一个与MAVS相互作用的线粒体电子传递链组分蛋白COX5B。通过过表达和基因缺失实验表明：该蛋白在RLRs抗病毒天然免疫中起着负调控作用，缺失该蛋白可以有效控制VSV病毒的复制。进一步的研究表明：过表达MAVS可以引起线粒体ROS水平的升高，而COX5B不仅抑制MAVS诱导的ROS水平升高，而且与自噬通路的重要蛋白ATG5相互作用，并共同调控MAVS聚集体的产生。此外，MAVS信号通路的激活又可以增强COX5B和ATG5蛋白水平的表达量，从而形成负反馈，进一步维持抗病毒天然免疫反应的平衡。
该研究首次发现MAVS可以影响线粒体ROS水平的变化，而线粒体电子传递链与自噬一起通过控制ROS水平共同调控抗病毒天然免疫的过程。这为进一步探索线粒体在抗病毒通路中的作用提供了新思路。
该成果于12月21日在线发表于PLoS Pathogens上。(生物谷Bioon.com)
doi:10.1371/journal.ppat.1003086
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COX5B Regulates MAVS-mediated Antiviral Signaling through Interaction with ATG5 and Repressing ROS Production
Yuanyuan Zhao equal contributor, Xiaofeng Sun equal contributor, Xuanli Nie, Liwei Sun, Tie-shan Tang, Dahua Chen, Qinmiao Sun
Innate antiviral immunity is the first line of the host defense system that rapidly detects invading viruses. Mitochondria function as platforms for innate antiviral signal transduction in mammals through the adaptor protein, MAVS. Excessive activation of MAVS-mediated antiviral signaling leads to dysfunction of mitochondria and cell apoptosis that likely causes the pathogenesis of autoimmunity. However, the mechanism of how MAVS is regulated at mitochondria remains unknown. Here we show that the Cytochrome c Oxidase (CcO) complex subunit COX5B physically interacts with MAVS and negatively regulates the MAVS-mediated antiviral pathway. Mechanistically, we find that while activation of MAVS leads to increased ROS production and COX5B expression, COX5B down-regulated MAVS signaling by repressing ROS production. Importantly, our study reveals that COX5B coordinates with the autophagy pathway to control MAVS aggregation, thereby balancing the antiviral signaling activity. Thus, our study provides novel insights into the link between mitochondrial electron transport system and the autophagy pathway in regulating innate antiviral immunity.
