Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis
Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis
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DOI：
10.1038/nm.3777
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发表时间：
2015-02-01
期刊：
影响因子：
82.9
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Palumbo-Zerr, Katrin;Zerr, Pawel;Distler, Joerg H. W.
间充质反应是组织修复的重要方面。然而，如果不能正确地终止这种修复过程，就会导致纤维化和器官功能障碍。阻断纤维化和恢复组织稳态的疗法尚未用于临床使用。在这里，我们将核受体NR 4A 1描述为转化生长因子-β（TGF-β）信号传导的内源性抑制剂，并作为抗纤维化治疗的潜在靶点。NR 4A 1将包含SP1、SIN 3A、CoREST、LSD 1和HDAC 1的阻遏物复合物募集至TGF-β靶基因，从而限制促纤维化TGF-β作用。尽管在生理伤口愈合中TGF-β的暂时上调诱导NR 4A 1表达并由此产生负反馈环，但纤维化疾病中TGF-β信号传导的持续激活使用AKT和HDAC依赖性机制来抑制NR 4A 1表达和激活。小分子NR 4A 1激动剂可以克服这种活性NR 4A 1的缺乏，并抑制小鼠实验诱导的皮肤、肺、肝和肾纤维化。我们的数据证明了NR 4A 1在TGF-β信号传导和纤维化中的调节作用，为靶向NR 4A 1治疗纤维化疾病提供了第一个概念证据。
Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-beta (TGF-beta) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-beta target genes, thereby limiting pro-fibrotic TGF-beta effects. Even though temporary upregulation of TGF-beta in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-beta signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-beta signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.