Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA.
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.
Huang
Bo
B
Department of Biochemistry, College of Medicine, MC-714, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Yang
Xiao-Dong
XD
Zhou
Ming-Ming
MM
Ozato
Keiko
K
Chen
Lin-Feng
LF
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D004257:DNA Polymerase II / Q000378:metabolism; D006801:Humans; D008239:Lysine; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D042863:Cyclin-Dependent Kinase 9; D004257:DNA Polymerase II; D008239:Lysine; D016328:NF-kappa B; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse