The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells
The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells
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DOI：
10.1038/ni.3230
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发表时间：
2015-09-01
影响因子：
30.5
通讯作者：
Knobeloch, Klaus-Peter
中科院分区：
文献类型：
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作者：
Dufner, Almut;Kisser, Agnes;Knobeloch, Klaus-Peter
泛素对蛋白质的修饰在免疫系统细胞中发挥着重要作用，并被各种功能不明确的去泛素化酶 (DUB) 所抵消。在这里，我们将泛素特异性蛋白酶 USP8 鉴定为 T 细胞抗原受体 (TCR) 信号体的调节成分，与接头 Gads 和调节分子 14-3-3 beta 3 相互作用。USP8 的半胱天冬酶依赖性加工在 TCR 刺激后发生。小鼠中 USP8 的 T 细胞特异性缺失表明，USP8 对于胸腺细胞成熟和由转录因子 Foxo1 介导的细胞因子受体 IL-7R α 编码基因的上调至关重要。 T细胞特异性USP8缺陷的小鼠会患上结肠炎，这种结肠炎是由T细胞稳态紊乱、肠道中CD8(+) γ δ T细胞占主导地位以及调节性T细胞功能受损所促进的。总的来说，我们的数据揭示了 USP8 作为 T 细胞中的免疫调节 DUB 的意想不到的作用。
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 14-3-3 beta 3. 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-7R alpha 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(+) gamma delta 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.