National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
Sci Rep. 2017 Jan 3;7:39986. doi: 10.1038/srep39986.
As members of bromodomain and extra-terminal motif protein family, bromodomain-containing proteins regulate a wide range of biological processes including protein scaffolding, mitosis, cell cycle progression and transcriptional regulation. The function of these bromodomain proteins (Brds) in innate immune response has been reported but the role of Brd3 remains unclear. Here we find that virus infection significantly downregulate Brd3 expression in macrophages and Brd3 knockout inhibits virus-triggered IFN-β production. Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection. Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. Therefore, our work indicated that Brd3 may act as a coactivator in IRF3/p300 transcriptional activation of Ifnb1 and provided new epigenetic mechanistic insight into the efficient activation of the innate immune response.
作为溴结构域和末端外显子基序蛋白家族的成员，含溴结构域蛋白调节广泛的生物学过程，包括蛋白质支架、有丝分裂、细胞周期进展和转录调控。这些溴结构域蛋白（Brds）在先天免疫反应中的功能已经被报道，但 Brd3 的作用仍不清楚。在这里，我们发现病毒感染显著下调巨噬细胞中的 Brd3 表达，并且 Brd3 敲除抑制病毒触发的 IFN-β 产生。Brd3 与 IRF3 和 p300 相互作用，增加 p300 介导的 IRF3 乙酰化，并增强病毒感染时 IRF3 与 p300 的结合。重要的是，Brd3 促进了 IRF3/p300 复合物向 Ifnb1 启动子的募集，并增加了 Ifnb1 启动子内组蛋白 3/组蛋白 4 的乙酰化，从而增强了 I 型干扰素的产生。因此，我们的工作表明 Brd3 可能作为 IRF3/p300 转录激活 Ifnb1 的共激活因子，并为先天免疫反应的有效激活提供了新的表观遗传机制见解。
