Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA

Mol Cell Biol. 2009 Mar;29(5):1375-87. doi: 10.1128/MCB.01365-08. Epub 2008 Dec 22.

Abstract

Acetylation of the RelA subunit of NF-kappaB, especially at lysine-310, is critical for the transcriptional activation of NF-kappaB and the expression of inflammatory genes. In this study, we demonstrate that bromodomains of Brd4 bind to acetylated lysine-310. Brd4 enhances transcriptional activation of NF-kappaB and the expression of a subset of NF-kappaB-responsive inflammatory genes in an acetylated lysine-310-dependent manner. Bromodomains of Brd4 and acetylated lysine-310 of RelA are both required for the mutual interaction and coactivation function of Brd4. Finally, we demonstrate that Brd4 further recruits CDK9 to phosphorylate C-terminal domain of RNA polymerase II and facilitate the transcription of NF-kappaB-dependent inflammatory genes. Our results identify Brd4 as a novel coactivator of NF-kappaB through specifically binding to acetylated lysine-310 of RelA. In addition, these studies reveal a mechanism by which acetylated RelA stimulates the transcriptional activity of NF-kappaB and the NF-kappaB-dependent inflammatory response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Line
  • Cyclin-Dependent Kinase 9 / metabolism
  • DNA Polymerase II / metabolism
  • Humans
  • Lysine
  • Mice
  • NF-kappa B / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Transcription Factor RelA / metabolism*
  • Transcription Factors / metabolism*
  • Transcriptional Activation

Substances

  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Transcription Factor RelA
  • Transcription Factors
  • Cyclin-Dependent Kinase 9
  • DNA Polymerase II
  • Lysine