线粒体-溶酶体互作对自发型MAVS聚集体的自噬降解调控

Mitochondrial MAVS aggregates are prion-like protein complexes that play an important function in activating antiviral innate immunity. Our recent work showed that in the absence of N-terminally truncated isoforms, MAVS is prone to spontaneous aggregation and able to induce proinflammatory cytokines, suggesting its potential involvement in immune homeostasis and autoimmune diseases; spontaneously aggregated MAVS is subjected to mitophagic degradation, implicating the interaction between mitochondrion and lysosome in the process. Based on these findings, we aim to explore how mitochondrion-lysosome interaction modulates the mitophagic degradation of MAVS aggregates, identify unknown key factors involved and then dissect the molecular mechanism underlying the signaling network involving lysosomes and mitochondria interaction. This project will also provide insight to the understanding of clearance of MAVS aggregates induced upon virus infection in cellular antiviral innate immune signaling and shed light into the diagnosis of related disorders and therapeutic development.

线粒体MAVS聚集体是细胞抗病毒天然免疫的功能性激活蛋白质复合体。我们实验室的前期工作，发现线粒体MAVS可自发聚集及其诱导产生过量炎症因子，表明其可影响机体免疫稳态和引起自身免疫性疾病；发现这种异常的线粒体MAVS聚集体可被自噬降解，提示其可能通过线粒体-溶酶体互作过程。本申请项目依据上述前期工作提示的重要线索和已构建线粒体自噬-溶酶体互作的前沿研究系统等基础上，深入探索线粒体-溶酶体互作对MAVS聚集体的自噬降解调控，着重确定细胞自发型MAVS聚集体的线粒体自噬与溶酶体降解关系、发现细胞自发型MAVS聚集体消除过程线粒体与溶酶体互作的关键分子和揭示其对细胞自发型MAVS聚集体的线粒体自噬或溶酶体降解的调控机制。该申请项目实施获得结果，既促进阐析细胞抗病毒天然免疫的感染型MAVS聚集体消除的生理机制和拓展研究相应细胞器互作的网络调控，也为相关疾病诊治、药物研发等提供理论依据和重要基础。

当病毒感染宿主细胞时，模式识别受体RIG-I识别并结合病毒的RNA，经过一系列信号转导之后，诱导线粒体蛋白质MAVS形成朊蛋白样多聚体，MAVS随之形成激活态并启动下游信号转导通路，最终产生I型干扰素和促炎因子来抑制病毒侵染。MAVS激活下游信号通路的具体的分子机制仍然未知。此项研究首先揭示MAVS-RegionⅢ需要形成多聚态才能够激活下游TBK1-IRF3支路，随后发现TRAF3IP3特异性地与激活状态的MAVS-RegionⅢ相互作用，同时也可以结合TRAF3；通过进一步的功能验证实验，发现在人源细胞中，TRAF3IP3响应病毒刺激而聚集到线粒体，与激活态的MAVS相互作用，促进MAVS招募下游的信号分子TRAF3，从而特异性地介导MAVS激活TBK1-IRF3支路，TRAF3IP3和IKK-NF-κB支路的激活无关。此外，在小鼠水平验证了这一机制，发现TRAF3IP3的缺失确实会对RNA病毒引起的天然免疫反应产生抑制作用，从而降低小鼠的抗病毒免疫力。这一研究成果揭示了MAVS招募下游信号分子的新机制，为后续深入研究MAVS下游信号通路打下基础。