Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex
Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex
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DOI：
10.15252/embj.201488447
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发表时间：
2014-10-16
期刊：
影响因子：
11.4
通讯作者：
Takeuchi, Osamu
中科院分区：
文献类型：
--
作者：
Tartey, Sarang;Matsushita, Kazufumi;Takeuchi, Osamu
先天免疫细胞中炎症基因的转录受到转录因子（包括 NF-kappa B 和染色质修饰剂）的协调调节。然而，目前尚不清楚微生物传感如何启动染色质重塑。在这里，我们发现 Akirin2（一种进化上保守的核蛋白）通过与 BRG1 相关因子 60 (BAF60) 蛋白以及 I kappa B-zeta 相互作用，桥接 NF-kappa B 和染色质重塑 SWI/SNF 复合物，I kappa B-zeta 与 NF-kappa B p50 亚基形成复合物。这些相互作用对于巨噬细胞中 Toll 样受体、RIG-I 和李斯特菌介导的促炎基因（包括 Il6 和 Il12b）的表达至关重要。一致地，有效清除李斯特菌感染需要 Akirin2。此外，Akirin2 和 I kappa B-zeta 募集至 Il6 启动子分别取决于 I kappa B-zeta 和 Akirin2 的存在，以调节染色质重塑。 BAF60 蛋白对于诱导 IL6 响应 LPS 刺激也是必需的。总的来说，I kappa B-zeta-Akirin2-BAF60 复合物在先天免疫细胞激活中物理连接 NF-kappa B 和 SWI/SNF 复合物。通过将 SWI/SNF 染色质重塑因子招募到 I kappa B-zeta（NF-kappa B 的转录共激活因子）中，保守的核蛋白 Akirin2 在针对病毒或细菌感染的先天免疫反应过程中刺激小鼠巨噬细胞中的促炎基因启动子。
Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-kappa B, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-kappa B and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as I kappa B-zeta, which forms a complex with the NF-kappa B p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and I kappa B-zeta recruitment to the Il6 promoter depend upon the presence of I kappa B-zeta and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the I kappa B-zeta-Akirin2-BAF60 complex physically links the NF-kappa B and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to I kappa B-zeta, transcriptional coactivator for NF-kappa B, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.