cGAS Is a Negative Regulator of RIG-I-Mediated IFN Response in Cyprinid Fish.

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.