Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IκBα
Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IκBα
复制标题
DOI：
10.1073/pnas.1700109114
复制
发表时间：
2017-05-16
影响因子：
11.1
通讯作者：
Chen, Lin-Feng
中科院分区：
文献类型：
--
作者：
Bao, Yan;Wu, Xuewei;Chen, Lin-Feng
含溴结构域因子 Brd4 已成为 NF-κ B 依赖性炎症基因表达的重要转录调节因子。然而，Brd4 在炎症反应中的体内生理功能仍不清楚。我们现在证明，髓系细胞中缺乏 Brd4 的小鼠能够抵抗 LPS 诱导的败血症，但更容易受到细菌感染。骨髓源性巨噬细胞 (BMDM) 的基因表达微阵列分析表明，Brd4 的缺失会降低大量 LPS 诱导的炎症基因的表达，同时逆转一小部分 LPS 抑制基因的表达，包括 MAP 激酶相互作用的丝氨酸/苏氨酸蛋白激酶 2 (Mknk2)。 Brd4 缺陷的 BMDM 在 LPS 刺激后表现出增强的 Mnk2 表达和相应的真核翻译起始因子 4E (eIF4E) 激活，导致多核糖体中 I.Ba mRNA 的翻译增加。增强的新合成 I.Ba 减少了 NF-κ B 与炎症基因启动子的结合，导致炎症基因表达和细胞因子产生减少。通过 Mnk2-eIF4E 途径调节 I.Ba 的翻译，Brd4 为 NF-κ B 依赖性炎症基因表达和炎症反应提供了额外的控制层。
Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-kappa B-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of I.Ba mRNA in polysomes. The enhanced newly synthesized I.Ba reduced the binding of NF-kappa B to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of I.Ba via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-kappa B-dependent inflammatory gene expression and inflammatory response.