The kinase CK1ɛ controls the antiviral immune response by phosphorylating the signaling adaptor TRAF3

Nat Immunol. 2016 Apr;17(4):397-405. doi: 10.1038/ni.3395. Epub 2016 Feb 29.

Abstract

The signaling adaptor TRAF3 is a highly versatile regulator of both innate immunity and adaptive immunity, but how its phosphorylation is regulated is still unknown. Here we report that deficiency in or inhibition of the conserved serine-threonine kinase CK1ɛ suppressed the production of type I interferon in response to viral infection. CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3. Consequently, CK1ɛ-deficient mice were more susceptible to viral infection. Our findings establish CK1ɛ as a regulator of antiviral innate immune responses and indicate a novel mechanism of immunoregulation that involves CK1ɛ-mediated phosphorylation of TRAF3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Casein Kinase 1 epsilon / antagonists & inhibitors
  • Casein Kinase 1 epsilon / genetics
  • Casein Kinase 1 epsilon / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • HEK293 Cells
  • HeLa Cells
  • Herpes Simplex / immunology
  • Herpesvirus 1, Human / immunology
  • Humans
  • Immunity, Innate / immunology*
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology
  • Interferon-beta / biosynthesis
  • Interferon-beta / immunology*
  • Mass Spectrometry
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein Serine-Threonine Kinases
  • Real-Time Polymerase Chain Reaction
  • Rhabdoviridae Infections / immunology
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / immunology*
  • Ubiquitination
  • Vesiculovirus / immunology
  • West Nile Fever / immunology
  • West Nile virus / immunology

Substances

  • Interferon Type I
  • TNF Receptor-Associated Factor 3
  • Interferon-beta
  • Tbk1 protein, mouse
  • Casein Kinase 1 epsilon
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human