A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression

Nature. 2003 Jun 5;423(6940):659-63. doi: 10.1038/nature01648.

Abstract

NF-kappaB is a principal transcriptional regulator of diverse cytokine-mediated processes and is tightly controlled by the IkappaB kinase complex (IKK-alpha/beta/gamma). IKK-beta and IKK-gamma are critical for cytokine-induced NF-kappaB function, whereas IKK-alpha is thought to be involved in other regulatory pathways. However, recent data suggest a role for IKK-alpha in NF-kappaB-dependent gene expression in response to cytokine treatment. Here we demonstrate nuclear accumulation of IKK-alpha after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation (ChIP) assays reveal that IKK-alpha was recruited to the promoter regions of NF-kappaB-regulated genes on stimulation with tumour-necrosis factor-alpha. Notably, NF-kappaB-regulated gene expression is suppressed by the loss of IKK-alpha and this correlates with a complete loss of gene-specific phosphorylation of histone H3 on serine 10, a modification previously associated with positive gene expression. Furthermore, we show that IKK-alpha can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. We propose that IKK-alpha is an essential regulator of NF-kappaB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure. These findings provide additional insight into the role of the IKK complex in NF-kappaB-regulated gene expression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Fibroblasts
  • Gene Deletion
  • Gene Expression Regulation* / drug effects
  • Histones / metabolism
  • I-kappa B Kinase
  • I-kappa B Proteins / genetics
  • Interleukin-6 / genetics
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / chemistry
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nucleosomes / drug effects
  • Nucleosomes / metabolism*
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Histones
  • I-kappa B Proteins
  • Interleukin-6
  • NF-kappa B
  • Nfkbia protein, mouse
  • Nucleosomes
  • RNA, Messenger
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse