IKKβ is an IRF5 kinase that instigates inflammation

Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17438-43. doi: 10.1073/pnas.1418516111. Epub 2014 Oct 17.

Abstract

The transcription factor interferon regulatory factor 5 (IRF5) is essential for the induction of inflammatory cytokines, but the mechanism by which IRF5 is activated is not well understood. Here we present evidence that the kinase IKKβ phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll-like receptors and retinoic acid-inducible gene I-like receptors. IKKβ phosphorylates mouse IRF5 at specific residues, including serine 445 (S446 in human IRF5 isoform 1), as evidenced by mass spectrometry analysis and detection with a phosphospecific antibody. Recombinant IKKβ phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production. Depletion or pharmacologic inhibition of IKKβ prevented IRF5 phosphorylation. These results indicate that IKKβ is an IRF5 kinase that instigates inflammation.

Keywords: IKK; IRF5; TLR; inflammation; phosphorylation.

Publication types

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

MeSH terms

  • Alanine / chemistry
  • Animals
  • Cytokines / metabolism
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / metabolism*
  • Inflammation / metabolism*
  • Interferon Regulatory Factors / metabolism*
  • Mass Spectrometry
  • Mice
  • Mutation
  • Phosphorylation
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Serine / chemistry

Substances

  • Cytokines
  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Irf5 protein, mouse
  • Serine
  • I-kappa B Kinase
  • IKBKB protein, human
  • Ikbkb protein, mouse
  • Alanine