Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
Nat Immunol. 2015 Sep;16(9):950-60. doi: 10.1038/ni.3230. Epub 2015 Jul 27.
The modification of proteins by ubiquitin has a major role in cells of the immune system and is counteracted by various deubiquitinating enzymes (DUBs) with poorly defined functions. Here we identified the ubiquitin-specific protease USP8 as a regulatory component of the T cell antigen receptor (TCR) signalosome that interacted with the adaptor Gads and the regulatory molecule 14-3-3β. Caspase-dependent processing of USP8 occurred after stimulation of the TCR. T cell-specific deletion of USP8 in mice revealed that USP8 was essential for thymocyte maturation and upregulation of the gene encoding the cytokine receptor IL-7Rα mediated by the transcription factor Foxo1. Mice with T cell-specific USP8 deficiency developed colitis that was promoted by disturbed T cell homeostasis, a predominance of CD8(+) γδ T cells in the intestine and impaired regulatory T cell function. Collectively, our data reveal an unexpected role for USP8 as an immunomodulatory DUB in T cells.
泛素化修饰的蛋白质在免疫系统细胞中起着重要作用，其功能由各种去泛素化酶（DUB）拮抗，但其功能尚不清楚。本文中，我们鉴定了泛素特异性蛋白酶 USP8 作为 T 细胞抗原受体（TCR）信号转导体的一个调节成分，与衔接蛋白 Gads 和调节分子 14-3-3β相互作用。TCR 刺激后，USP8 发生依赖于半胱天冬酶的加工。在小鼠中，特异性敲除 USP8 发现，USP8 对胸腺细胞成熟和转录因子 Foxo1 介导的细胞因子受体 IL-7Rα 的基因上调是必需的。USP8 特异性敲除 T 细胞的小鼠发生结肠炎，这是由 T 细胞稳态紊乱、肠道中 CD8(+)γδ T 细胞增多和调节性 T 细胞功能受损所促进的。总之，我们的数据揭示了 USP8 作为 T 细胞中一种免疫调节 DUB 的意外作用。
