Liu Wei, Li Jing, Zheng Weinan, Shang Yingli, Zhao Zhendong, Wang Shanshan, Bi Yuhai, Zhang Shuang, Xu Chongfeng, Duan Ziyuan, Zhang Lianfeng, Wang Yue L, Jiang Zhengfan, Liu Wenjun, Sun Lei
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Elife. 2017 Jun 8;6:e24425. doi: 10.7554/eLife.24425.
RIG-I is a key cytosolic pattern recognition receptor that interacts with MAVS to induce type I interferons (IFNs) against RNA virus infection. In this study, we found that cyclophilin A (CypA), a peptidyl-prolyl isomerase, functioned as a critical positive regulator of RIG-I-mediated antiviral immune responses. Deficiency of CypA impaired RIG-I-mediated type I IFN production and promoted viral replication in human cells and mice. Upon Sendai virus infection, CypA increased the interaction between RIG-I and its E3 ubiquitin ligase TRIM25, leading to enhanced TRIM25-mediated K63-linked ubiquitination of RIG-I that facilitated recruitment of RIG-I to MAVS. In addition, CypA and TRIM25 competitively interacted with MAVS, thereby inhibiting TRIM25-induced K48-linked ubiquitination of MAVS. Taken together, our findings reveal an essential role of CypA in boosting RIG-I-mediated antiviral immune responses by controlling the ubiquitination of RIG-I and MAVS.
视黄酸诱导基因I（RIG-I）是一种关键的胞质模式识别受体，它与线粒体抗病毒信号蛋白（MAVS）相互作用，以诱导I型干扰素（IFN）来抵御RNA病毒感染。在本研究中，我们发现肽基脯氨酰异构酶亲环素A（CypA）作为RIG-I介导的抗病毒免疫反应的关键正向调节因子发挥作用。CypA的缺失损害了RIG-I介导的I型干扰素产生，并促进了病毒在人类细胞和小鼠中的复制。在仙台病毒感染后，CypA增加了RIG-I与其E3泛素连接酶TRIM25之间的相互作用，导致TRIM25介导的RIG-I的K63连接的泛素化增强，这促进了RIG-I向MAVS的募集。此外，CypA和TRIM25与MAVS竞争性相互作用，从而抑制TRIM25诱导的MAVS的K48连接的泛素化。综上所述，我们的研究结果揭示了CypA在通过控制RIG-I和MAVS的泛素化来增强RIG-I介导的抗病毒免疫反应中的重要作用。
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