Brd4 Coactivates Transcriptional Activation of NF-κB via Specific Binding to Acetylated RelA
Brd4 Coactivates Transcriptional Activation of NF-κB via Specific Binding to Acetylated RelA
复制标题
DOI：
10.1128/mcb.01365-08
复制
发表时间：
2009-03-01
影响因子：
5.3
通讯作者：
Chen, Lin-Feng
中科院分区：
文献类型：
--
作者：
Huang, Bo;Yang, Xiao-Dong;Chen, Lin-Feng
NF-kappa B 的 RelA 亚基的乙酰化，尤其是赖氨酸 310 的乙酰化，对于 NF-kappa B 的转录激活和炎症基因的表达至关重要。在这项研究中，我们证明了 Brd4 的溴结构域与乙酰化赖氨酸 310 结合。 Brd4 以乙酰化赖氨酸 310 依赖性方式增强 NF-kappa B 的转录激活和 NF-kappa B 响应性炎症基因子集的表达。 Brd4 的溴结构域和 RelA 的乙酰化赖氨酸 310 都是 Brd4 相互作用和共激活功能所必需的。最后，我们证明 Brd4 进一步招募 CDK9 磷酸化 RNA 聚合酶 II 的 C 端结构域并促进 NF-κ B 依赖性炎症基因的转录。我们的结果确定 Brd4 通过与 RelA 的乙酰化赖氨酸 310 特异性结合而成为 NF-kappa B 的新型共激活剂。此外，这些研究揭示了乙酰化 RelA 刺激 NF-κ B 转录活性和 NF-κ B 依赖性炎症反应的机制。
Acetylation of the RelA subunit of NF-kappa B, especially at lysine-310, is critical for the transcriptional activation of NF-kappa B 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-kappa B and the expression of a subset of NF-kappa B-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-kappa B-dependent inflammatory genes. Our results identify Brd4 as a novel coactivator of NF-kappa B 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-kappa B and the NF-kappa B-dependent inflammatory response.