ZFIN ID: ZDB-PUB-150717-7
pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation
Du, J., Zhang, D., Zhang, W., Ouyang, G., Wang, J., Liu, X., Li, S., Ji, W., Liu, W., Xiao, W.
Date: 2015
Source: Journal of immunology (Baltimore, Md. : 1950)   195(4): 1782-90 (Journal)
Registered Authors: Ji, Wei, Liu, Wei, Ouyang, Gang, Wang, Jing, Xiao, Wuhan, Zhang, Wei
Keywords: none
MeSH Terms:
  • Adaptor Proteins, Signal Transducing/chemistry
  • Adaptor Proteins, Signal Transducing/metabolism*
  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Gene Knockout Techniques
  • Humans
  • Immunity, Innate
  • Proteasome Endopeptidase Complex/metabolism*
  • Protein Binding
  • Proteolysis
  • Signal Transduction*
  • Von Hippel-Lindau Tumor Suppressor Protein/genetics
  • Von Hippel-Lindau Tumor Suppressor Protein/metabolism*
  • Zebrafish
PubMed: 26179906 Full text @ J. Immunol.
The von Hippel-Lindau (VHL) gene is a well-defined tumor suppressor linked to human heredity cancer syndromes. As a component of the VHL-elongin B/C E3 ligase complex, pVHL performs its tumor function by targeting proteins for proteasomal degradation. It is largely unknown whether pVHL functions in antiviral immunity. In this article, we identify that pVHL negatively regulates innate antiviral immunity, which acts mainly by inducing degradation of mitochondrial antiviral-signaling protein (MAVS, also known as Cardif, IPS-1, or VISA). Overexpression of pVHL abrogated the cellular response to viral infection, whereas knockdown of pVHL exerted the opposite effect. pVHL targeted the K420 residue of MAVS to catalyze the formation of K48-linked polyubiquitin chains, leading to proteasomal degradation of MAVS. After viral infection, Mavs levels remained low in wild type zebrafish embryos but became much higher in vhl-deficient (vhl(-/-)) zebrafish embryos. Higher MAVS levels correlated with a greatly exaggerated antiviral response. In this work, we demonstrate that pVHL exhibits a previously unknown role in innate antiviral immunity.