天然免疫系統(tǒng)是機體抵抗病原微生物入侵的第一道防線，它首先通過模式識別受體(PRRs)與病原體相關分子模式(PAMPs)相互識別,，進一步激活一系列的免疫反應,。同時，宿主細胞通過多種方式負調(diào)節(jié)天然免疫反應的信號通路,，以保證信號傳導的平衡,，進而防止過度免疫反應對宿主細胞造成損傷。在抗RNA病毒天然免疫中,，主要有兩類PRRs: TLRs和RLRs,。MAVS作為RLRs介導的抗病毒免疫信號通路中的重要接頭蛋白，通過C端的TM結(jié)構域定位于線粒體外膜，它的線粒體定位對于其功能的發(fā)揮至關重要,。盡管以往對于MAVS的分子調(diào)控機制進行了較多的研究,，但是人們對MAVS定位于線粒體外膜的功能還很不清楚。
中科院動物研究所孫欽秒研究組通過酵母雙雜篩選得到一個與MAVS相互作用的線粒體電子傳遞鏈組分蛋白COX5B,。通過過表達和基因缺失實驗表明：該蛋白在RLRs抗病毒天然免疫中起著負調(diào)控作用,，缺失該蛋白可以有效控制VSV病毒的復制。進一步的研究表明：過表達MAVS可以引起線粒體ROS水平的升高,，而COX5B不僅抑制MAVS誘導的ROS水平升高,，而且與自噬通路的重要蛋白ATG5相互作用，并共同調(diào)控MAVS聚集體的產(chǎn)生,。此外,，MAVS信號通路的激活又可以增強COX5B和ATG5蛋白水平的表達量，從而形成負反饋,，進一步維持抗病毒天然免疫反應的平衡,。
該研究首次發(fā)現(xiàn)MAVS可以影響線粒體ROS水平的變化，而線粒體電子傳遞鏈與自噬一起通過控制ROS水平共同調(diào)控抗病毒天然免疫的過程,。這為進一步探索線粒體在抗病毒通路中的作用提供了新思路,。
該成果于12月21日在線發(fā)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.
