2. Academic Validation
  3. ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

  • Nat Commun. 2023 May 19;14(1):2859. doi: 10.1038/s41467-023-38605-3.
Xiangling Xiao # 1 2,  Jie Shi # 1 2,  Chuan He # 1 2,  Xia Bu 3,  Yishuang Sun 1 2,  Minling Gao 1 2,  Bolin Xiang 1 2,  Wenjun Xiong 1 2,  Panpan Dai 1,  Qi Mao 1 2,  Xixin Xing 1 2,  Yingmeng Yao 1 2,  Haisheng Yu 1 2,  Gaoshan Xu 1 2,  Siqi Li 4,  Yan Ren 5,  Baoxiang Chen 6,  Congqing Jiang 6,  Geng Meng 7,  Yu-Ru Lee 8,  Wenyi Wei 9,  Gordon J Freeman 3,  Conghua Xie 10,  Jinfang Zhang 11 12
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
  • 2 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 Department of Biology, University of Copenhagen, Copenhagen, 2100, Denmark.
  • 5 Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6 Department of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 7 College of Veterinary Medicine, China Agricultural University, Beijing, 100094, China.
  • 8 Institute of Biomedical Sciences, Academia Sinica, Taipei, 115201, Taiwan.
  • 9 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
  • 10 Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China. chxie_65@whu.edu.cn.
  • 11 Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China. jinfang_zhang@whu.edu.cn.
  • 12 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China. jinfang_zhang@whu.edu.cn.
  • # Contributed equally.
PMID: 37208329 DOI: 10.1038/s41467-023-38605-3
Abstract

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting Cancer immune evasion. While ubiquitin E3 Ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the Ubiquitin-Specific Protease 5 (USP5) as a bona fide Deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.

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