Lang Xueting, Tang Tiantian, Jin Tengchuan, Ding Chen, Zhou Rongbin, Jiang Wei
Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei 230027, China.
J Exp Med. 2017 Feb;214(2):459-473. doi: 10.1084/jem.20160592. Epub 2016 Dec 28.
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.
黑色素瘤分化相关基因5（MDA5）作为一种细胞质双链RNA传感器，可激活I型干扰素信号通路，在抗病毒天然免疫中发挥关键作用，但其激活机制尚不清楚。在此，我们发现TRIM65特异性地与MDA5相互作用，并促进MDA5在赖氨酸743处发生K63连接的泛素化，这对MDA5的寡聚化和激活至关重要。TRIM65基因敲除消除了MDA5激动剂或脑心肌炎病毒（EMCV）诱导的干扰素调节因子3（IRF3）激活及I型干扰素产生，但对维甲酸诱导基因I（RIG-I）、Toll样受体3（TLR3）或环鸟苷酸-腺苷酸合成酶信号通路无影响。重要的是，与对照相比，TRIM65基因敲除小鼠对EMCV感染更敏感，且在体内无法产生I型干扰素。总体而言，我们的结果确定TRIM65是MDA5信号通路的一个重要组成部分，并提供了生理学证据表明泛素化对MDA5寡聚化和激活很重要。
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