A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation
A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation
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DOI：
10.1073/pnas.0405786101
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发表时间：
2004-10-05
影响因子：
11.1
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
Ogawa, S;Lozach, J;Glass, CK
核受体共抑制因子（NCoR）以及被称为视黄酸和甲状腺激素受体沉默中介体（SMRT）的相关因子是多蛋白复合物的关键组成部分，这些复合物介导未结合配体的核受体的主动抑制作用。近期研究表明，NCoR和SMRT能够与其他几类DNA结合转录因子相互作用并对其产生抑制效应，但这些相互作用的生理重要性尚未确定。在此，对巨噬细胞中由NCoR调控的内源性转录程序的研究显示，NCoR作为激活蛋白（AP）-1依赖性基因网络的转录检查点，该基因网络调控包括炎症、细胞迁移和胶原分解代谢在内的多种生物学过程，NCoR缺失会导致AP - 1靶基因去抑制。NCoR共抑制复合物对c - Jun与c - Jun/c - Fos异二聚体的交换施加主动阻断，靶向缺失c - Jun基因座会导致在基础条件下AP - 1靶基因上的NCoR复合物丢失。NCoR的检查点功能通过c - jun的信号依赖性磷酸化得以解除，这会通过招募一种特定的泛素化复合物引导NCoR/HDAC3/TBL1/TBLR1复合物的去除，这是c - Jun/c - Fos异二聚体默认结合和转录激活的先决条件。为实现对炎症信号转录反应的适当动态范围而需要检查点功能这一情况，可能也被其他调控多种内稳态和发育过程的信号依赖性转录因子所利用。
The nuclear receptor corepressor (NCoR) and the related factor known as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) are essential components of multiprotein complexes that mediate active repression by unliganded nuclear receptors. Recent studies suggest that NCoR and SMRT can interact with and exert repressive effects on several other classes of DNA-binding transcription factors, but the physiological importance of these interactions has not been established. Here, investigation of endogenous transcriptional programs regulated by NCoR in macrophages reveals that NCoR acts as a transcriptional checkpoint for activator protein (AP)-1-dependent gene networks that regulate diverse biological processes including inflammation, cell migration, and collagen catabolism, with loss of NCoR, resulting in derepression of AP-1 target genes. The NCoR corepressor complex imposes an active block of exchange of c-Jun for c-Jun/c-Fos heterodimers, with targeted deletion of the c-Jun locus, resulting in loss of NCoR complexes from AP-1 target genes under basal conditions. The checkpoint function of NCoR is relieved by signal-dependent phosphorylation of c-jun, which directs removal of NCoR/HDAC3/TBL1/TBLR1 complexes through recruitment of a specific ubiquitylation complex, as a prerequisite to the default binding of c-Jun/c-Fos heterodimers and transcriptional activation. The requirement for a checkpoint function to achieve the appropriate dynamic range of transcriptional responses to inflammatory signals is likely to be used by other signal-dependent transcription factors that regulate diverse homeostatic and developmental processes.