A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ
A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ
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DOI：
10.1038/nature03988
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发表时间：
2005-09-29
期刊：
影响因子：
64.8
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
Pascual, G;Fong, AL;Glass, CK
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）在脂肪形成和葡萄糖稳态中具有重要作用，是胰岛素增敏药物的分子靶点（1-3）。尽管PPAR-gamma激动剂通过核因子κ B（NF-κ B）靶基因的反式阻遏来拮抗炎症反应的能力与抗糖尿病（4）和抗动脉粥样硬化作用（5）相关，但其机制仍知之甚少。在这里，我们报告的分子途径，其中PPAR-gamma抑制小鼠巨噬细胞炎症反应基因的转录激活的鉴定。该途径的初始步骤涉及PPAR-gamma配体结合结构域的配体依赖性SUMO化，其将PPAR-gamma靶向至炎性基因启动子上的核受体辅阻遏物（NCoR）-组蛋白脱乙酰酶-3（HDAC 3）复合物。这反过来又阻止了泛素化/19 S蛋白酶体机制的招募，该机制通常介导基因激活所需的辅阻遏物复合物的信号依赖性去除。因此，NCoR复合物不能从启动子中清除，靶基因保持在抑制状态。这种机制为激动剂结合的核受体如何从转录激活因子转化为调节免疫和稳态的NF-κ B靶基因的启动子特异性阻遏物提供了解释。
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has essential roles in adipogenesis and glucose homeostasis, and is a molecular target of insulin-sensitizing drugs(1-3). Although the ability of PPAR-gamma agonists to antagonize inflammatory responses by transrepression of nuclear factor kappa B (NF-kappa B) target genes is linked to antidiabetic(4) and antiatherogenic actions(5), the mechanisms remain poorly understood. Here we report the identification of a molecular pathway by which PPAR-gamma represses the transcriptional activation of inflammatory response genes in mouse macrophages. The initial step of this pathway involves ligand-dependent SUMOylation of the PPAR-gamma ligand-binding domain, which targets PPAR-gamma to nuclear receptor corepressor (NCoR)-histone deacetylase-3 (HDAC3) complexes on inflammatory gene promoters. This in turn prevents recruitment of the ubiquitylation/19S proteosome machinery that normally mediates the signal-dependent removal of corepressor complexes required for gene activation. As a result, NCoR complexes are not cleared from the promoter and target genes are maintained in a repressed state. This mechanism provides an explanation for how an agonist-bound nuclear receptor can be converted from an activator of transcription to a promoter-specific repressor of NF-kappa B target genes that regulate immunity and homeostasis.