Mitofusin 2 Inhibits Mitochondrial Antiviral Signaling
Mitofusin 2 Inhibits Mitochondrial Antiviral Signaling
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DOI：
10.1126/scisignal.2000287
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发表时间：
2009-08-18
影响因子：
7.3
通讯作者：
Koshiba, Takumi
中科院分区：
文献类型：
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作者：
Yasukawa, Kai;Oshiumi, Hiroyuki;Koshiba, Takumi
对病毒感染的先天免疫反应涉及多个信号传导步骤的激活，最终产生 I 型干扰素 (IFN)。线粒体抗病毒信号传导（MAVS）是一种线粒体外膜衔接蛋白，在此过程中发挥着重要作用。在这里，我们报道线粒体融合蛋白 2 (Mfn2) 与 MAVS 相互作用来调节抗病毒免疫。 Mfn2 的过度表达导致视黄酸诱导基因 I (RIG-I) 和黑色素瘤分化相关基因 5 (MDA-5)（病毒 RNA 的两种胞质传感器）的抑制，以及 MAVS 介导的转录因子干扰素调节因子 3 (IRF-3) 和核因子 kappa B (NF-kappa B) 的激活。相反，内源性Mfn2的缺失增强了病毒诱导的IFN-β的产生，从而减少了病毒复制。结构功能分析表明，Mfn2 通过七肽重复区域与 MAVS 的羧基末端区域相互作用，为线粒体抗病毒反应的调节提供了结构视角。我们的结果表明，Mfn2 作为抗病毒信号传导的抑制剂，其功能可能与其在线粒体动力学中的作用不同。
The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor kappa B (NF-kappa B). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-beta and thereby decreased viral replication. Structure-function analysis revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. Our results suggest that Mfn2 acts as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics.