Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment.
Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment.
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RORγT在赖氨酸446处的泛量通过控制共激活因子募集而限制了Th17的分化。
DOI：
10.4049/jimmunol.1600548
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发表时间：
2016-08-15
期刊：
影响因子：
--
通讯作者：
Sun Z
中科院分区：
文献类型：
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作者：
He Z;Wang F;Ma J;Sen S;Zhang J;Gwack Y;Zhou Y;Sun Z
转录因子视黄酸相关孤儿受体γ t（RORγt）指导辅助性T细胞17（Th17）的分化。Th17细胞介导导致自身免疫性疾病的病理性免疫应答，包括银屑病和多发性硬化症。以往的研究主要集中在RORγt靶基因及其在Th17分化中的功能。在此，我们研究了RORγt的转录后调控，并确定了一个功能性泛素化位点，赖氨酸446（K446）。将K446突变为精氨酸（K446R）以防止泛素化，极大地增强了类固醇受体辅激活因子1（SRC1）的募集，SRC1是RORγt活性的关键辅激活因子。相应地，K446R突变增强了Th17分化。我们还发现泛素特异性蛋白酶15（USP 15）与RORγt相互作用，从K446中去除泛素，并通过增强共激活剂SRC 1的募集来刺激RORγt活性。USP15的敲除或失活USP15的表达损害Th17分化，表明USP15介导的RORγt去泛素化在Th17分化中具有积极作用。因此，K446的泛素化通过抑制共激活因子SRC 1的募集来限制RORγ t介导的Th17分化。我们的研究将为靶向RORγt泛素化途径以限制Th17介导的自身免疫的治疗的发展提供信息。
The transcription factor retinoid acid-related orphan receptor gamma t (RORγt) directs the differentiation of T helper 17 (Th17) cells. Th17 cells mediate pathological immune responses responsible for autoimmune diseases, including psoriasis and multiple sclerosis. Previous studies have focused on RORγt target genes and their function in Th17 differentiation. Here, we studied post-transcriptional regulation of RORγt and identified a functional ubiquitination site, lysine 446 (K446). Mutation of K446 to arginine (K446R) to prevent ubiquitination greatly enhanced recruitment of steroid receptor co-activator 1 (SRC1), a co-activator critical for RORγt activity. Correspondingly, the K446R mutation potentiated Th17 differentiation. We also showed that the ubiquitin specific protease 15 (USP15) interacted with RORγt, removed ubiquitin from K446, and stimulated RORγt activity by enhancing co-activator SRC1 recruitment. Knockdown of USP15 or expression of inactive USP15 impaired Th17 differentiation, suggesting a positive role for USP15-mediated deubiquitination of RORγt in Th17 differentiation. Therefore, ubiquitination of K446 limits RORγt-mediated Th17 differentiation by inhibiting the recruitment of co-activator SRC1. Our study will inform the development of treatments that target RORγt ubiqutination pathways to limit Th17-mediated autoimmunity.