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

PKACs attenuate innate antiviral response by phosphorylating VISA and priming it for MARCH5-mediated degradation.
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Yan BR, Zhou L, Hu MM, Li M, Lin H, Yang Y, Wang YY, Shu HB,


Yan BR, Zhou L, Hu MM, Li M, Lin H, Yang Y, Wang YY, Shu HB, (click to view)

Yan BR, Zhou L, Hu MM, Li M, Lin H, Yang Y, Wang YY, Shu HB,

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PLoS pathogens 2017 09 2113(9) e1006648 doi 10.1371/journal.ppat.1006648
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.

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