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

Cellular & Molecular Immunology volumeĀ 20,Ā pages 252ā€“263 (2023)Cite this article

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Abstract

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 RORĪ³t 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.

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Acknowledgements

We thank all members of the Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, for helpful discussions and input.

Funding

This work was funded by grants from the National Natural Science Foundation of China (81971805, 81901614, 81901659, 32070906, 82072384, 82074160, and 82272239).

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Author notes

  1. These authors contributed equally: Xiaotong Zhu, Peng Wang, Xiaoxia Zhan.

Authors and Affiliations

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

    Xiaotong Zhu,Ā Yuping Zhang,Ā Qinghong Yu,Ā Ligang JieĀ &Ā Shengfeng Hu

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

    Peng Wang

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

    Xiaoxia ZhanĀ &Ā Laisheng Li

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

    Junli Sheng,Ā Shitong He,Ā Yitian Chen,Ā Dingnai Nie,Ā Xiaolong You,Ā Haiyan MaiĀ &Ā Shengfeng Hu

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

    Junli Sheng,Ā Shitong He,Ā Yitian Chen,Ā Dingnai Nie,Ā Xiaolong You,Ā Haiyan MaiĀ &Ā Shengfeng Hu

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Contributions

SFH, GLJ, LSL and PW designed the research; XTZ, PW, XXZ, YPZ, JLS, STH, YTC, DNN, XLY, and HYM conducted the research; XTZ, QHY, LGJ and SFH analyzed data; XTZ, XXZ and SFH wrote the paper; GLJ, LSL, PW and SFH provided essential reagents or materials; and SFH, GLJ and LSL as the corresponding authors conducted the experiments. All authors read and approved the final paper.

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Correspondence to Laisheng Li, Ligang Jie or Shengfeng Hu.

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All procedures followed were in accordance with protocols approved by the Medical Ethics Board and the Biosafety Management Committee of Southern Medical University.

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Zhu, X., Wang, P., Zhan, X. et al. USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ. Cell Mol Immunol 20, 252ā€“263 (2023). https://doi.org/10.1038/s41423-022-00969-9

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