Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways
Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways
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DOI：
10.1101/gad.1773109
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发表时间：
2009-03-15
影响因子：
10.5
通讯作者：
Glass, Christopher K.
中科院分区：
文献类型：
--
作者：
Ghisletti, Serena;Huang, Wendy;Glass, Christopher K.
对细菌或病毒感染的先天免疫反应需要大量炎症反应基因从稳定/抑制状态快速转换到活跃转录状态，但潜在的抑制/去抑制机制仍不清楚。在这里，我们报道，虽然核受体辅阻遏子(NCoR)和维甲酸和甲状腺激素受体(SMRT)的沉默介导物(SMRT)辅阻遏子在巨噬细胞的广泛炎症反应基因上建立抑制检查点，并且几乎是肝X受体(LXRs)所有反转录抑制活动所必需的，但它们可以分别通过c-Jun或ETS阻遏物TEL选择性招募，建立NCoR特异的、SMRT特异的和NCoR/SMRT依赖的启动子。出乎意料的是，NCoR和SMRT与NCoR/SMRT依赖的启动子的结合经常是相互依赖的，这建立了LXR转录抑制所需的两种蛋白质，并使选择性靶向NCoR或SMRT的炎症信号通路也能去抑制/激活NCoR/SMRT依赖的基因。这些发现揭示了一种组合的、基于辅抑制子的策略，用于整合炎症和抗炎信号，这些信号在免疫和动态平衡中发挥重要作用。
Innate immune responses to bacterial or viral infection require rapid transition of large cohorts of inflammatory response genes from poised/repressed to actively transcribed states, but the underlying repression/derepression mechanisms remain poorly understood. Here, we report that, while the nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor ( SMRT) corepressors establish repression checkpoints on broad sets of inflammatory response genes in macrophages and are required for nearly all of the transrepression activities of liver X receptors (LXRs), they can be selectively recruited via c-Jun or the Ets repressor Tel, respectively, establishing NCoR-specific, SMRT-specific, and NCoR/SMRT-dependent promoters. Unexpectedly, the binding of NCoR and SMRT to NCoR/SMRT-dependent promoters is frequently mutually dependent, establishing a requirement for both proteins for LXR transrepression and enabling inflammatory signaling pathways that selectively target NCoR or SMRT to also derepress/activate NCoR/SMRT-dependent genes. These findings reveal a combinatorial, corepressor-based strategy for integration of inflammatory and anti-inflammatory signals that play essential roles in immunity and homeostasis.