Zhou Yu, Lei Yi, Lu Long-Feng, Chen Dan-Dan, Zhang Can, Li Zhuo-Cong, Zhou Xiao-Yu, Li Shun, Zhang Yong-An
State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China.
Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
J Immunol. 2021 Aug 1;207(3):784-798. doi: 10.4049/jimmunol.2100075. Epub 2021 Jul 21.
In mammals, cyclic GMP-AMP synthase (cGAS) recognizes cytosolic dsDNA to induce the type I IFN response. However, the functional role of cGAS in the IFN response of fish remains unclear or controversial. In this study, we report that cGAS orthologs from crucian carp (cGAS) and grass carp (cGAS) target the dsRNA sensor retinoic acid-inducible gene I (RIG-I) for negative regulation of the IFN response. First, poly(deoxyadenylic-deoxythymidylic) acid-, polyinosinic-polycytidylic acid-, and spring viremia of carp virus-induced IFN responses were impaired by overexpression of cGAS and cGAS. Then, cGAS and cGAS interacted with RIG-I and MAVS and inhibited RIG-I- and MAVS-mediated IFN induction. Moreover, the K63-linked ubiquitination of RIG-I and the interaction between RIG-I and MAVS were attenuated by cGAS and cGAS. Finally, cGAS and cGAS decreased RIG-I-mediated the cellular antiviral response and facilitated viral replication. Taken together, data in this study identify cGAS and cGAS as negative regulators in RIG-I-like receptor signaling, which extends the current knowledge regarding the role of fish cGAS in the innate antiviral response.
在哺乳动物中，环状GMP-AMP合酶（cGAS）识别胞质双链DNA以诱导I型干扰素反应。然而，cGAS在鱼类干扰素反应中的功能作用仍不明确或存在争议。在本研究中，我们报道鲫鱼（cGAS）和草鱼（cGAS）的cGAS直系同源物靶向双链RNA传感器视黄酸诱导基因I（RIG-I），对干扰素反应进行负调控。首先，过表达cGAS和cGAS会损害聚（脱氧腺苷酸-脱氧胸苷酸）、聚肌苷酸-聚胞苷酸以及鲤鱼春季病毒血症病毒诱导的干扰素反应。然后，cGAS和cGAS与RIG-I和线粒体抗病毒信号蛋白（MAVS）相互作用，并抑制RIG-I和MAVS介导的干扰素诱导。此外，cGAS和cGAS减弱了RIG-I的K63连接泛素化以及RIG-I与MAVS之间的相互作用。最后，cGAS和cGAS降低了RIG-I介导的细胞抗病毒反应，并促进了病毒复制。综上所述，本研究数据确定cGAS和cGAS为RIG-I样受体信号通路中的负调控因子，这扩展了目前关于鱼类cGAS在先天性抗病毒反应中作用的认识。
