SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival

Mol Cell. 2004 Oct 22;16(2):245-55. doi: 10.1016/j.molcel.2004.10.010.

Abstract

Understanding how signaling cascades stimulate chromatin-remodeling events through derepression is one of the foremost questions in the transcription field. Here, we demonstrate that NF-kappaB transcription requires IKKalpha to phosphorylate SMRT on chromatin, stimulating the exchange of corepressor for coactivator complexes. IKKalpha-induced phosphorylation coincides with a loss of chromatin-associated SMRT and HDAC3 and with nuclear export of the SMRT corepressor, events required for expression of the NF-kappaB-regulated cIAP-2 and IL-8 genes. Although SMRT derepression corresponds with the recruitment of TBL1/TBLR1, this complex alone is insufficient to relieve repression. Using a nonphosphorylatable SMRT protein, we demonstrate that IKKalpha-induced phosphorylation is required to recruit 14-3-3epsilon and Ubc5 for SMRT derepression. Failure of IKKalpha to stimulate the removal of SMRT from chromatin inhibits the recruitment of NF-kappaB to promoters, blocking transcription and sensitizing cells to apoptosis. Our work provides evidence that IKKalpha orchestrates SMRT derepression, a prerequisite for NF-kappaB transcription and survival.

Publication types

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

MeSH terms

  • Cell Nucleus / metabolism
  • Chromatin / metabolism
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / physiology
  • Humans
  • I-kappa B Kinase
  • Laminin / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nuclear Receptor Co-Repressor 2
  • Phosphorylation
  • Protein Transport / physiology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / metabolism*
  • Serine / metabolism
  • Transcription, Genetic / physiology*

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Laminin
  • NCOR2 protein, human
  • NF-kappa B
  • Nuclear Receptor Co-Repressor 2
  • Repressor Proteins
  • Serine
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human