Differential regulation of IKK alpha-mediated activation of IRF3/7 by NIK

Mol Immunol. 2008 Apr;45(7):1926-34. doi: 10.1016/j.molimm.2007.10.034. Epub 2007 Dec 18.

Abstract

Type I interferons (IFNs) are critical mediators of the innate immune system to defend viral infection. Interferon regulatory factor (IRF) 3 and IRF7 are transcription factors that play critical roles in type I IFN production in response to viral infection. It has been shown that the protein kinase I kappaB kinase alpha (IKK alpha) is critically involved in IRF7 activation and IFN-alpha production in Toll-like receptor 7/9 (TLR7/9) signaling cascades. However, overexpression of IKK alpha does not activate the IFN-alpha promoters. Here we show that the protein kinase nuclear factor kappaB-inducing kinase (NIK) confers IKK alpha the ability to activate IRF3/7. Previous studies have shown that NIK phosphorylates IKK alpha at Ser-176 and Ser-180 residues, and mutation of each of the two residues to glutamate, which mimics its phosphorylation, caused constitutive activation of NF-kappaB. However, mutation of the two serine residues has differential effects on IKK alpha-mediated activation of IRF3/7. While IKK alpha(S176E) constitutively activates IRF3/7, IKK alpha(S180E) losses its ability to activate IRF3/7. These findings suggest that IKK alpha-mediated activation of NF-kappaB and IRF3/7 are differentially regulated by NIK, and NIK plays an important role in TLR7/9-mediated IFN-alpha production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • I-kappa B Kinase / metabolism*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / metabolism*
  • Interferon Type I / genetics
  • Mice
  • Myeloid Differentiation Factor 88 / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • TNF Receptor-Associated Factor 6 / metabolism

Substances

  • Antiviral Agents
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Myeloid Differentiation Factor 88
  • TNF Receptor-Associated Factor 6
  • Phosphoserine
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • NF-kappa B kinase