Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation

Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.

Abstract

During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Vesicular Transport / chemistry
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Humans
  • I-kappa B Kinase / metabolism
  • Interferon Regulatory Factor-3 / chemistry
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon-alpha / biosynthesis
  • Interferon-beta / biosynthesis
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Multimerization
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / metabolism
  • Sendai virus / physiology
  • Serine / metabolism
  • Signal Transduction
  • Ubiquitination
  • Vesiculovirus / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon-alpha
  • MAVS protein, human
  • MPYS protein, mouse
  • Membrane Proteins
  • Recombinant Proteins
  • STING protein, human
  • TICAM1 protein, human
  • Serine
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase