Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression

Nature. 2003 Jun 5;423(6940):655-9. doi: 10.1038/nature01576.

Abstract

Cytokine-induced activation of the IkappaB kinases (IKK) IKK-alpha and IKK-beta is a key step involved in the activation of the NF-kappaB pathway. Gene-disruption studies of the murine IKK genes have shown that IKK-beta, but not IKK-alpha, is critical for cytokine-induced IkappaB degradation. Nevertheless, mouse embryo fibroblasts deficient in IKK-alpha are defective in the induction of NF-kappaB-dependent transcription. These observations raised the question of whether IKK-alpha might regulate a previously undescribed step to activate the NF-kappaB pathway that is independent of its previously described cytoplasmic role in the phosphorylation of IkappaBalpha. Here we show that IKK-alpha functions in the nucleus to activate the expression of NF-kappaB-responsive genes after stimulation with cytokines. IKK-alpha interacts with CREB-binding protein and in conjunction with Rel A is recruited to NF-kappaB-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. These results define a new nuclear role of IKK-alpha in modifying histone function that is critical for the activation of NF-kappaB-directed gene expression.

MeSH terms

  • Animals
  • CREB-Binding Protein
  • Fibroblasts
  • Gene Deletion
  • Gene Expression Regulation / drug effects*
  • HeLa Cells
  • Histones / metabolism*
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / genetics
  • Interleukin-8 / genetics
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / chemistry
  • NF-kappa B / metabolism
  • Nuclear Proteins / metabolism
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / metabolism
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Histones
  • I-kappa B Proteins
  • Interleukin-8
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse