Sensing of viral RNA by RIG-I-like receptors initiates innate antiviral response, which is mediated by the central adaptor VISA. How the RIG-I-VISA-mediated antiviral response is terminated at the late phase of infection is enigmatic. Here we identified the protein kinase A catalytic (PKAC) subunits α and β as negative regulators of RNA virus-triggered signaling in a redundant manner. Viral infection up-regulated cellular cAMP levels and activated PKACs, which then phosphorylated VISA at T54. This phosphorylation abrogated virus-induced aggregation of VISA and primed it for K48-linked polyubiquitination and degradation by the E3 ligase MARCH5, leading to attenuation of virus-triggered induction of downstream antiviral genes. PKACs-deficiency or inactivation by the inhibitor H89 potentiated innate immunity to RNA viruses in cells and mice. Our findings reveal a critical mechanism of attenuating innate immune response to avoid host damage at the late phase of viral infection by the house-keeping PKA kinase.

RIG-I样受体对病毒RNA的感应可引发先天性抗病毒反应，这是由中央衔接子VISA介导的。RIG-I-VISA介导的抗病毒反应在感染后期如何终止是未知的。在这里，我们以冗余的方式确定了蛋白激酶A催化（PKAC）亚基α和β为RNA病毒触发信号的负调节剂。病毒感染会上调细胞cAMP水平并激活PKAC，然后在T54处使VISA磷酸化。这种磷酸化消除了病毒诱导的VISA聚集，并通过E3连接酶MARCH5引发了K48连接的多泛素化和降解，从而导致病毒触发的下游抗病毒基因诱导作用减弱。PKAC缺乏或抑制剂H89失活增强了细胞和小鼠对RNA病毒的固有免疫力。