E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses

Nat Commun. 2017 Mar 13:8:14654. doi: 10.1038/ncomms14654.

Abstract

Viruses can escape from host recognition by degradation of RIG-I or interference with the RIG-I signalling to establish persistent infections. However, the mechanisms by which host cells stabilize RIG-I protein for avoiding its degradation are largely unknown. We report here that, upon virus infection, the E3 ubiquitin ligase FBXW7 translocates from the nucleus into the cytoplasm and stabilizes RIG-I. FBXW7 interacts with SHP2 and mediates the degradation and ubiquitination of SHP2, thus disrupting the SHP2/c-Cbl complex, which mediates RIG-I degradation. When infected with VSV or influenza A virus, FBXW7 conditional knockout mice (Lysm+FBXW7f/f) show impaired antiviral immunity. FBXW7-deficient macrophages have decreased RIG-I protein levels and type-I interferon signalling. Furthermore, PBMCs from RSV-infected children have reduced FBXW7 mRNA levels. Our results identify FBXW7 as an important interacting partner for RIG-I. These findings provide insights into the function of FBXW7 in antiviral immunity and its related clinical significance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Child
  • DEAD Box Protein 58 / genetics*
  • DEAD Box Protein 58 / immunology
  • F-Box-WD Repeat-Containing Protein 7 / deficiency
  • F-Box-WD Repeat-Containing Protein 7 / genetics*
  • F-Box-WD Repeat-Containing Protein 7 / immunology
  • Gene Expression Regulation
  • HEK293 Cells
  • Host-Pathogen Interactions*
  • Humans
  • Influenza A virus / immunology*
  • Influenza A virus / pathogenicity
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Macrophages / immunology*
  • Macrophages / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Primary Cell Culture
  • Protein Stability
  • Protein Transport
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / immunology
  • Proteolysis
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / immunology
  • RAW 264.7 Cells
  • Respiratory Syncytial Viruses / immunology*
  • Respiratory Syncytial Viruses / pathogenicity
  • Ubiquitination
  • Vesiculovirus / immunology*
  • Vesiculovirus / pathogenicity

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • Interferon Type I
  • Proto-Oncogene Proteins c-cbl
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • Cbl protein, mouse