PKACs attenuate innate antiviral response by phosphorylating VISA and priming it for MARCH5-mediated degradation

• DOI: 10.1371/journal.ppat.1006648
• Publication Date: 2017-09-21T14:00:07Z
• Authors: Bing-Ru Yan; Lu Zhou; Ming-Ming Hu; Mi Li; Heng Lin; Yan Yang; Yan-Yi Wang; Hong-Bing Shu
• Keywords: 0301 basic medicine; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; QH301-705.5; Ubiquitin-Protein Ligases; Immunoblotting; Membrane Proteins; RC581-607; Respirovirus Infections; Sendai virus; Immunity, Innate; 3. Good health; Mice; 03 medical and health sciences; HEK293 Cells; Animals; Humans; Immunoprecipitation; Immunologic diseases. Allergy; Biology (General); Phosphorylation; Research Article; Adaptor Proteins, Signal Transducing

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.