Ghisletti Serena, Huang Wendy, Jepsen Kristen, Benner Chris, Hardiman Gary, Rosenfeld Michael G, Glass Christopher K
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
Genes Dev. 2009 Mar 15;23(6):681-93. doi: 10.1101/gad.1773109.
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.
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迅速从准备/抑制状态转变为活跃转录状态，但其潜在的抑制/去抑制机制仍知之甚少。在此，我们报告，虽然核受体共抑制因子（NCoR）和视黄酸及甲状腺激素受体沉默介质（SMRT）共抑制因子在巨噬细胞中对广泛的炎症反应基因建立抑制检查点，并且是肝脏X受体（LXR）几乎所有反式抑制活性所必需的，但它们可分别通过c-Jun或Ets抑制因子Tel被选择性招募，从而建立NCoR特异性、SMRT特异性以及NCoR/SMRT依赖性启动子。出乎意料的是，NCoR和SMRT与NCoR/SMRT依赖性启动子的结合常常相互依赖，这使得LXR反式抑制需要这两种蛋白，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依赖性基因。这些发现揭示了一种基于共抑制因子的组合策略，用于整合在免疫和体内平衡中起关键作用的炎症和抗炎信号。
