The Optimal Corepressor Function of Nuclear Receptor Corepressor (NCoR) for Peroxisome Proliferator-activated Receptor γ Requires G Protein Pathway Suppressor 2
The Optimal Corepressor Function of Nuclear Receptor Corepressor (NCoR) for Peroxisome Proliferator-activated Receptor γ Requires G Protein Pathway Suppressor 2
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DOI：
10.1074/jbc.m114.598797
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发表时间：
2015-02-06
影响因子：
4.8
通讯作者：
Zhang, Jinsong
中科院分区：
文献类型：
--
作者：
Guo, Chun;Li, Yali;Zhang, Jinsong
核受体辅阻遏物（NCoR）对过氧化物酶体增殖物激活受体γ（PPAR γ）依赖性转录的抑制对于体内PPAR γ靶基因的稳态表达很重要。目前的模型表明，NCoR介导的抑制需要其与抑制构象中的PPAR γ直接相互作用。然而，先前的研究表明，DNA结合的PPAR γ与NCoR的直接、高亲和力缔合不相容，因为PPAR γ具有采用活性构象的固有能力。在这里，我们表明，NCoR获得的能力，通过G蛋白途径抑制因子2（GPS2），一个组件的NCoR辅阻遏复合物抑制活性的过氧化物酶体增殖物激活受体γ介导的转录。与NCoR不同，GPS2可以识别并结合PPAR γ的活性状态。在GPS2缺陷的小鼠胚胎成纤维细胞中，GPS2的缺失显著降低了NCoR对PPAR γ的辅阻遏物功能，导致PPAR γ靶基因的组成性激活和细胞的自发脂肪形成。然而，GPS2对于由未配体的甲状腺激素受体γ或不能采用活性构象的aPPAR γ突变体介导的阻遏是不利的。这项研究表明，GPS2，虽然NCoR的内在阻遏功能，可以介导一种新的辅阻遏物阻遏途径，使NCoR直接抑制活性的PPAR γ介导的转录，这是重要的最佳辅阻遏物功能的NCoR的PPAR γ。有趣的是，GPS2依赖性抑制特异性靶向PPARgamma，但不靶向PPARalpha或PPARdelta。因此，GPS2可以作为一个独特的目标，以操纵疾病中的PPAR γ信号。
Repression of peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent transcription by the nuclear receptor corepressor (NCoR) is important for homeostatic expression of PPAR gamma target genes in vivo. The current model states that NCoR-mediated repression requires its direct interaction with PPAR gamma in the repressive conformation. Previous studies, however, have shown that DNA-bound PPAR gamma is incompatible with a direct, high-affinity association with NCoR because of the inherent ability of PPAR gamma to adopt the active conformation. Here we show that NCoR acquires the ability to repress active PPAR gamma-mediated transcription via G protein pathway suppressor 2 (GPS2), a component of the NCoR corepressor complex. Unlike NCoR, GPS2 can recognize and bind the active state of PPAR gamma. In GPS2-deficient mouse embryonic fibroblast cells, loss of GPS2 markedly reduces the corepressor function of NCoR for PPAR gamma, leading to constitutive activation of PPAR gamma target genes and spontaneous adipogenesis of the cells. GPS2, however, is dispensable for repression mediated by unliganded thyroid hormone receptor gamma or aPPAR gamma mutant unable to adopt the active conformation. This study shows that GPS2, although dispensable for the intrinsic repression function of NCoR, can mediate a novel corepressor repression pathway that allows NCoR to directly repress active PPAR gamma-mediated transcription, which is important for the optimal corepressor function of NCoR for PPAR gamma. Interestingly, GPS2-dependent repression specifically targets PPAR gamma but not PPAR alpha or PPAR delta. Therefore, GPS2 may serve as a unique target to manipulate PPAR gamma signaling in diseases.