Ubiquitination of cGAS by TRAF6 regulates anti-DNA viral innate immune responses

Biochem Biophys Res Commun. 2019 Jun 30;514(3):659-664. doi: 10.1016/j.bbrc.2019.05.022. Epub 2019 May 8.

Abstract

cGAS-STING (stimulator of interferon genes) signaling is crucial for the recognition of cytoplasmic double-stranded DNA by host cells and consequently activating innate immune response by promoting the production cGAMP and type I interferon. However, it remains elusive how the cGAS enzymatic activity is regulated dynamically. In this study, we identified TRAF6 as a regulator of cGAS mediated anti-viral innate immunity. Our data showed that either ectopic expression or knockdown of TRAF6 modulates the double strand DNA induced expression of interferon-responsive genes. Mechanistically, TRAF6 specifically promotes cGAS activation by targeting cGAS for ubiquitination. Knockdown of TRAF6 results in a decrease in cGAS-induced IFNβ production when cells were infected with herpes simplex virus-1 (HSV-1). Together, our data identified TRAF6 as a positive regulator of cGAS-STING pathway by regulating cGAS activity.

Keywords: Innate immunity; TRAF6; Ubiquitination; cGAS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • HEK293 Cells
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / metabolism
  • Membrane Proteins / metabolism
  • Nucleotidyltransferases / metabolism*
  • Polyubiquitin / metabolism
  • Protein Binding
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Ubiquitination*
  • Vero Cells

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • STING1 protein, human
  • TNF Receptor-Associated Factor 6
  • Polyubiquitin
  • Nucleotidyltransferases
  • cGAS protein, human