Mitochondrial Membrane Potential Is Required for MAVS-Mediated Antiviral Signaling
Mitochondrial Membrane Potential Is Required for MAVS-Mediated Antiviral Signaling
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DOI：
10.1126/scisignal.2001147
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发表时间：
2011-02-01
影响因子：
7.3
通讯作者：
Kawabata, Shun-ichiro
中科院分区：
文献类型：
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作者：
Koshiba, Takumi;Yasukawa, Kai;Kawabata, Shun-ichiro
线粒体是经历融合和裂变循环的动态细胞器，是真核细胞的动力源，也参与哺乳动物的细胞先天抗病毒免疫。线粒体抗病毒免疫取决于细胞质视黄酸诱导基因 I (RIG-I) 样受体 (RLR) 信号通路的激活以及称为 MAVS（线粒体抗病毒信号）的线粒体外膜接头蛋白的参与。我们发现，由于线粒体融合蛋白 1 (Mfn1) 和线粒体融合蛋白 2 (Mfn2) 的靶向缺失而缺乏线粒体融合能力的细胞在应对病毒感染时表现出干扰素和促炎细胞因子的诱导受损，导致病毒复制增加。相比之下，Mfn1 或 Mfn2 无效突变的细胞保留了 RLR 诱导的抗病毒反应。我们还发现线粒体膜电位 (Delta Psi(m)) 降低与抗病毒反应降低相关。 Delta Psi(m)的消散并不影响MAVS下游转录因子干扰素调节因子3的激活，这表明Delta Psi(m)和MAVS在RLR信号通路的同一阶段偶联。我们的结果证明线粒体的生理功能在先天抗病毒免疫中发挥着关键作用。
Mitochondria, dynamic organelles that undergo cycles of fusion and fission, are the powerhouses of eukaryotic cells and are also involved in cellular innate antiviral immunity in mammals. Mitochondrial antiviral immunity depends on activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway and the participation of a mitochondrial outer membrane adaptor protein called MAVS (mitochondrial antiviral signaling). We found that cells that lack the ability to undergo mitochondrial fusion as a result of targeted deletion of both mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) exhibited impaired induction of interferons and proinflammatory cytokines in response to viral infection, resulting in increased viral replication. In contrast, cells with null mutations in either Mfn1 or Mfn2 retained their RLR-induced antiviral responses. We also found that a reduced mitochondrial membrane potential (Delta Psi(m)) correlated with the reduced antiviral response. The dissipation in Delta Psi(m) did not affect the activation of the transcription factor interferon regulatory factor 3 downstream of MAVS, which suggests that Delta Psi(m) and MAVS are coupled at the same stage in the RLR signaling pathway. Our results provide evidence that the physiological function of mitochondria plays a key role in innate antiviral immunity.