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About the Authors:
Bing-Ru Yan
Roles Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
Affiliations College of Life Sciences, Wuhan University, Wuhan, China, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China
Lu Zhou
Roles Investigation
Affiliations College of Life Sciences, Wuhan University, Wuhan, China, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China
Ming-Ming Hu
Roles Formal analysis, Investigation
Affiliation: Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China
Mi Li
Roles Investigation, Methodology
Affiliations College of Life Sciences, Wuhan University, Wuhan, China, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China
Heng Lin
Roles Investigation
Affiliations College of Life Sciences, Wuhan University, Wuhan, China, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China
Yan Yang
Roles Investigation
Affiliation: Wuhan Institute of Virology, State Key Laboratory of Virology, Chinese Academy of Sciences, Wuhan, China
Yan-Yi Wang
Roles Formal analysis, Project administration, Supervision
Affiliation: Wuhan Institute of Virology, State Key Laboratory of Virology, Chinese Academy of Sciences, Wuhan, China
Hong-Bing Shu
Roles Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
* E-mail: [email protected]
Affiliations College of Life Sciences, Wuhan University, Wuhan, China, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China
ORCID http://orcid.org/0000-0001-9102-3272Abstract
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 [alpha] and [Beta] 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.
Author summary
VISA is a central adaptor protein required for innate immune response to...