USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ
USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ
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USP1 通过去泛素化和稳定 TAZ 调节 Th17 细胞和 Treg 细胞的相互分化
DOI：
10.1038/s41423-022-00969-9
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发表时间：
2023-01-05
影响因子：
24.1
通讯作者：
Hu，Shengfeng
中科院分区：
文献类型：
--
作者：
Zhu，Xiaotong;Wang，Peng;Hu，Shengfeng
炎性辅助性T细胞17 （Th17）和免疫抑制调节性T细胞（Treg）之间的平衡对于维持人体免疫稳态至关重要，并且在健康条件下受到严格调节。越来越多的研究报道去泛素酶（deubiquitinases, DUBs）在调节Th17-和treg细胞分化中起着至关重要的作用。然而，只有一小部分DUBs在Th17-和treg细胞分化中的生物学功能是明确的。在这项研究中，我们发现泛素特异性肽酶1 （USP1）是CD4+ t细胞分化的重要调节因子。USP1促进th17细胞分化，但减弱treg细胞分化，从而促进炎症性疾病的发展。在机制上，CD4+T细胞中的USP1增强了rorγ - T的活性，但在体外和体内通过去泛素化和TAZ的稳定促进了Foxp3的蛋白酶体降解。值得注意的是，USP1/UAF1去泛素酶复合物的特异性抑制剂ML323在体外和体内抑制Th17细胞分化，促进Treg细胞分化，这表明ML323可能是治疗Th17和Treg细胞失衡相关疾病的有希望的候选药物。我们的研究强调了USP1在调节适应性免疫反应中的关键作用，并提示USP1可能是治疗与Th17和Treg细胞失衡相关疾病的药物靶点。
The balance between inflammatory T helper type 17 (Th17) and immunosuppressive regulatory T (Treg) cells is critical for maintaining immune homeostasis in the human body and is tightly regulated under healthy conditions. An increasing number of studies have reported that deubiquitinases (DUBs) play a vital role in regulating Th17- and Treg-cell differentiation. However, the biological functions of only a small fraction of DUBs in Th17- and Treg-cell differentiation are well defined. In this study, we identified ubiquitin-specific peptidase 1 (USP1) as a vital regulator of CD4+T-cell differentiation. USP1 promoted Th17-cell differentiation but attenuated Treg-cell differentiation, thereby promoting the development of inflammatory diseases. Mechanistically, USP1 in CD4+T cells enhanced the activity of RORγt but promoted the proteasomal degradation of Foxp3 through deubiquitination and stabilization of TAZ in vitro and in vivo. Notably, ML323, a specific inhibitor of the USP1/UAF1 deubiquitinase complex, inhibited Th17-cell differentiation and promoted Treg-cell differentiation in vitro and in vivo, indicating that ML323 might be a promising candidate for the treatment of diseases associated with an imbalance between Th17 and Treg cells. Our study highlights the critical role of USP1 in regulating adaptive immune responses and suggests that USP1 might be a drug target for the treatment of diseases associated with an imbalance between Th17 and Treg cells.