Abstract

AbstractAcetylation of the RelA subunit of NF-κB, especially at lysine-310, is critical for the transcriptional activation of NF-κB 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-κB and the expression of a subset of NF-κB-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-κB-dependent inflammatory genes. Our results identify Brd4 as a novel coactivator of NF-κB 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-κB and the NF-κB-dependent inflammatory response. ACKNOWLEDGMENTSWe thank W. C. Greene for providing the anti-acetylated lysine-310 antibodies, R. Goodman and R. Tapping for the gift of reagents, and members in the Chen lab for discussion.This study was supported in part by ICR provided by the University of Illinois at Urbana-Champaign and Biomedical Research Grant from American Lung Association. L.-F.C. is the recipient of an Arthritis Foundation Investigator Award.