Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch

J Biol Chem. 2007 Aug 3;282(31):22816-22. doi: 10.1074/jbc.M703019200. Epub 2007 May 25.

Abstract

The transcription factor interferon regulatory factor 3 (IRF-3) regulates genes in the innate immune response. IRF-3 is activated through phosphorylation by the kinases IKK epsilon and/or TBK1. Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300. The precise role of the different phosphorylation sites has remained controversial. Using purified proteins we show that TBK1 can directly phosphorylate full-length IRF-3 in vitro. Phosphorylation at residues in site 2 (Ser(396)-Ser(405)) alleviates autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitates phosphorylation at site 1 (Ser(385) or Ser(386)). Phosphorylation at site 1 is, in turn, required for IRF-3 dimerization. The data support a two-step phosphorylation model for IRF-3 activation mediated by TBK1.

MeSH terms

  • Animals
  • Baculoviridae / metabolism
  • Binding Sites
  • Cell Line
  • Dimerization
  • Humans
  • Hydrogen Bonding
  • Insecta
  • Interferon Regulatory Factor-3 / metabolism*
  • Models, Biological
  • Mutation
  • Peptides / chemistry
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism

Substances

  • Interferon Regulatory Factor-3
  • Peptides
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human