USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ

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外文摘要：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.

外文关键词：

USP1TAZTh17Treg

作者：

Xiaotong Zhu、Peng Wang、Xiaoxia Zhan、Yuping Zhang、Junli Sheng、Shitong He、Yitian Chen、Dingnai Nie、Xiaolong You、Haiyan Mai、Qinghong Yu、Laisheng Li、Ligang Jie、Shengfeng Hu

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作者单位：

Department of Rheumatology and Clinical Immunology,Zhujiang Hospital,Southern Medical University,Guangzhou,China

Department of Emergency Medicine,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,China

Department of Laboratory Medicine,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China

Institute of Molecular Immunology,School of Laboratory Medicine and Biotechnology,Southern Medical University,Guangzhou,Guangdong,China

Provincial Key Laboratory of Immune Regulation and Immunotherapy,School of Laboratory Medicine and Biotechnology,Southern Medical University,Guangzhou,Guangdong,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

项目编号：

81971805819016148190165932070906820723848207416082272239

出版年：

2023

DOI：

10.1038/s41423-022-00969-9

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(3)

参考文献量48