Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses
Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses
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DOI：
10.1038/s41467-019-12632-5
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发表时间：
2019-10-11
影响因子：
16.6
通讯作者：
Ichinohe, Takeshi
中科院分区：
文献类型：
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作者：
Moriyama, Miyu;Koshiba, Takumi;Ichinohe, Takeshi
胞质线粒体DNA（mtDNA）激活cGAS介导的抗病毒免疫反应，但RNA病毒刺激mtDNA释放的机制仍不清楚。在这里，我们表明，流感病毒M2或脑心肌炎病毒（EMCV）2B蛋白的病毒孔蛋白活性触发线粒体DNA易位到细胞质中的MAVS依赖的方式。虽然流感病毒诱导的胞质mtDNA刺激cGAS和DDX41依赖的先天免疫应答，但流感病毒的非结构蛋白1（NS1）与mtDNA缔合以逃避STING依赖的抗病毒免疫。STING依赖的抗病毒信号通过间隙连接在相邻细胞中放大。此外，我们发现流感病毒的STING依赖性识别对于限制病毒在体内的复制至关重要。我们的研究结果显示了流感病毒刺激mtDNA释放的机制，并强调了DNA传感途径在限制流感病毒复制中的重要性。
Cytosolic mitochondrial DNA (mtDNA) activates cGAS-mediated antiviral immune responses, but the mechanism by which RNA viruses stimulate mtDNA release remains unknown. Here we show that viroporin activity of influenza virus M2 or encephalomyocarditis virus (EMCV) 2B protein triggers translocation of mtDNA into the cytosol in a MAVS-dependent manner. Although influenza virus-induced cytosolic mtDNA stimulates cGAS- and DDX41-dependent innate immune responses, the nonstructural protein 1 (NS1) of influenza virus associates with mtDNA to evade the STING-dependent antiviral immunity. The STING-dependent antiviral signaling is amplified in neighboring cells through gap junctions. In addition, we find that STING-dependent recognition of influenza virus is essential for limiting virus replication in vivo. Our results show a mechanism by which influenza virus stimulates mtDNA release and highlight the importance of DNA sensing pathway in limiting influenza virus replication.