TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity.
TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity.
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DOI：
10.1084/jem.20160592
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Jiang W
中科院分区：
文献类型：
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作者：
Lang X;Tang T;Jin T;Ding C;Zhou R;Jiang W
Lang等人。确定E3连接酶TRIM65是MDA-5信号通路的重要组成部分，并提供确凿的证据表明泛素化在MDA5寡聚和激活中的重要性。MDA5作为胞质双链RNA感受器，激活I型干扰素信号通路，在抗病毒先天免疫中发挥重要作用，但MDA5的激活机制尚不清楚。在这里，我们发现TRIM65与MDA5特异地相互作用，并促进K63连接的MDA5赖氨酸743的泛素化，这对MDA5的齐聚和激活至关重要。Trim65缺乏可使MDA5激动剂或脑心肌炎病毒(EMCV)诱导的干扰素调节因子3(IRF3)激活和I型干扰素产生取消，但不影响维甲酸诱导的I(RIG-I)、Toll样受体3(TLR3)或环状GMP-AMP合酶信号通路。重要的是，Trim65−/−小鼠比对照组更容易感染EMCV，并且在体内不能产生I型干扰素。总之，我们的结果确认TRIM65是MDA5信号通路的重要组成部分，并提供了生理证据表明泛素化对MDA5的寡聚和激活是重要的。
Lang et al. identify E3 ligase TRIM65 as an essential component for the MDA-5 signaling pathway and provide solid evidence showing the importance of ubiquitination in MDA5 oligomerization and activation. MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)–induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid–inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65−/− mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation.