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pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation

Juan Du1, Dawei Zhang1, Wei Zhang1

  • 1Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, People's Republic of China; and.

Journal of Immunology (Baltimore, Md. : 1950)
|July 17, 2015
PubMed

Insights

The von Hippel-Lindau (VHL) protein suppresses innate antiviral immunity by degrading the mitochondrial antiviral-signaling protein (MAVS). Loss of VHL enhances antiviral responses, revealing a new role for VHL in immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • The von Hippel-Lindau (VHL) gene is a known tumor suppressor involved in hereditary cancer syndromes.
  • The pVHL protein, part of the VHL-elongin B/C E3 ligase complex, targets proteins for proteasomal degradation.
  • The role of pVHL in antiviral immunity remains largely unexplored.

Purpose of the Study:

  • To investigate the function of pVHL in innate antiviral immunity.
  • To determine if pVHL regulates the mitochondrial antiviral-signaling protein (MAVS).

Main Methods:

  • Investigated pVHL's effect on cellular response to viral infection via overexpression and knockdown.
  • Identified MAVS as a target of pVHL-induced degradation.
  • Utilized vhl-deficient zebrafish embryos to assess MAVS levels and antiviral response post-infection.
  • Analyzed MAVS ubiquitination at the K420 residue.

Main Results:

  • pVHL negatively regulates innate antiviral immunity.
  • pVHL induces the degradation of MAVS by catalyzing K48-linked polyubiquitination at the K420 residue.
  • Overexpression of pVHL impairs antiviral responses, while pVHL knockdown enhances them.
  • vhl-deficient zebrafish embryos exhibit higher MAVS levels and exaggerated antiviral responses after viral infection.

Conclusions:

  • pVHL plays a significant, previously unrecognized role in suppressing innate antiviral immunity.
  • pVHL targets MAVS for proteasomal degradation, thereby dampening the antiviral response.
  • Modulating VHL function could be a strategy for enhancing antiviral immunity.

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