Nature Communications (May 2023)
ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
- Xiangling Xiao,
- Jie Shi,
- Chuan He,
- Xia Bu,
- Yishuang Sun,
- Minling Gao,
- Bolin Xiang,
- Wenjun Xiong,
- Panpan Dai,
- Qi Mao,
- Xixin Xing,
- Yingmeng Yao,
- Haisheng Yu,
- Gaoshan Xu,
- Siqi Li,
- Yan Ren,
- Baoxiang Chen,
- Congqing Jiang,
- Geng Meng,
- Yu-Ru Lee,
- Wenyi Wei,
- Gordon J. Freeman,
- Conghua Xie,
- Jinfang Zhang
Affiliations
- Xiangling Xiao
- 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
- Jie Shi
- 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
- Chuan He
- 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
- Xia Bu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Yishuang Sun
- 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
- Minling Gao
- 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
- Bolin Xiang
- 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
- Wenjun Xiong
- 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
- Panpan Dai
- 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
- Qi Mao
- 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
- Xixin Xing
- 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
- Yingmeng Yao
- 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
- Haisheng Yu
- 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
- Gaoshan Xu
- 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
- Siqi Li
- Department of Biology, University of Copenhagen
- Yan Ren
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine
- Baoxiang Chen
- Department of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University
- Congqing Jiang
- Department of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University
- Geng Meng
- College of Veterinary Medicine, China Agricultural University
- Yu-Ru Lee
- Institute of Biomedical Sciences, Academia Sinica
- Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School
- Gordon J. Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- Conghua Xie
- 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
- Jinfang Zhang
- 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
- DOI
- https://doi.org/10.1038/s41467-023-38605-3
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 19
Abstract
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.
