Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt
Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt
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DOI：
10.4049/jimmunol.1401451
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发表时间：
2015-05-01
影响因子：
4.4
通讯作者：
Li, Bin
中科院分区：
文献类型：
--
作者：
Yang, Jing;Xu, Peng;Li, Bin
ROR γ t是控制炎性Th 17的发展和功能的关键转录因子。调节RORgt稳定性的机制仍不清楚。我们报告说，Th 17细胞高度表达去泛素化酶泛素特异性蛋白酶（USP）4，这是维持RORgt和Th 17细胞功能所必需的。用来自中国传统药物的化合物vialinin A抑制USP 4的催化活性，抑制了Th 17分化。USP 4与RORgt的K48连接的多聚泛素化相互作用并去泛素化，从而促进ROR γ t功能和IL-17 A转录。有趣的是，TGF-β加IL-6增强了ROR γ t的USP 4介导的去泛素化。此外，USP 4和IL-17 mRNA，而不是RORgt mRNA，在风湿性心脏病患者的CD 4（+）T细胞中显著升高。因此，USP 4可能是治疗Th 17调节的自身免疫性疾病的新的治疗靶点。
ROR gamma t is a key transcription factor that controls the development and function of inflammatory Th17. The mechanisms that regulate RORgt stability remain unclear. We report that Th17 cells highly express the deubiquitinase ubiquitin-specific protease (USP) 4, which is essential for maintaining RORgt and Th17 cell function. Inhibition of the catalytic activity of USP4 with vialinin A, a compound derived from Chinese traditional medicine, dampened Th17 differentiation. USP4 interacted and deubiquitinated K48-linked polyubiquitination of RORgt, thereby promoting ROR gamma t function and IL-17A transcription. Interestingly, TGF-beta plus IL-6 enhanced USP4-mediated deubiquitination of ROR gamma t. Moreover, USP4 and IL-17 mRNA, but not RORgt mRNA, were significantly elevated in CD4(+) T cells from patients with rheumatic heart disease. Thus, USP4 could be a novel therapeutic target for the treatment of Th17-modulated autoimmune diseases.