Abstract
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.
Highlights
Innate immune response is the first line of host defense against invading microbial pathogens
We found that PKACα and PKACβ markedly inhibited VISA-mediated activation of the IFN-β promotor in HEK293 cells (Fig 1, panel A)
VISA-deficient HEK293 cells reconstituted with VISA or its mutants were infected with Sendai virus (SeV) (MOI = 1) for the indicated times before co-immunoprecipitation and immunoblot analysis. (E) Effects of knockdown of AIP4, MARCH5 or RNF5 on PKACα-induced phosphorylation and degradation of VISA
Summary
Innate immune response is the first line of host defense against invading microbial pathogens. The structurally conserved components of microbes called pathogen-associated molecular patterns (PAMPs) are recognized by host pattern-recognition receptors (PRRs), which initiates signaling pathways that lead to induction of type I interferons (IFNs), proinflammatory cytokines and other downstream effector genes [1].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
