ArticleNature communications2023
ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.
Erratum issuedOpen access · goldAbstract read
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Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 72 papers.
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72citing papers in PubMed
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72 citing papers in PubMed, 73 citations in OpenAlex.
- Protein arginine methylation and ubiquitination: A prominent crosstalk and its functions in cancer.Genes & diseases · 2026Review
- SEC14L2 contributes to tumor progression by enhancing USP5-driven RBM3 deubiquitination in pancreatic ductal adenocarcinoma.Oncogene · 2026Article
- In vivo CRISPR screens identify dual functions of DNMT3A in mediating tumor immune evasion.Nature communications · 2026Article
- USP5 acts as a proteolytic switch to control SDE2 function via UBL-directed cleavage.Nature communications · 2026Article
- Cardiomyocyte OTUD7b drives diabetic cardiomyopathy via deubiquitinating and stabilizing TAK1.Acta pharmacologica Sinica · 2026Article
- BRCC3 promotes progression and immune evasion in non-small cell lung cancer through regulation of PD-L1 and B7-H3.Journal of molecular histology · 2026Article
- Protein modification systems as cancer biomarkers and therapeutic targets.Precision clinical medicine · 2026Review
- Review
- DDX5 (p68) and UbE2T as emerging superior cancer therapeutic targets: dual molecular glue target degradation by FL118 for conquering difficult-to-treat cancers.Journal of experimental & clinical cancer research : CR · 2026Review
- USP5 in cancer: a therapeutic window into metabolism and drug resistance.Journal of translational medicine · 2026Review
- Ubiquitin-centered post-translational modification crosstalk orchestrates tumor immunity and immunotherapy response.Experimental hematology & oncology · 2026Review
- Posttranscriptional regulation of PD-1 by PRMT5/WDR77 complex shapes T cell effector function and antitumor immunity.The Journal of clinical investigation · 2026Article
- USP5 inhibition stimulates immunogenic ferroptosis that enhances immunotherapy in diffuse large B-cell lymphoma.Cell communication and signaling : CCS · 2026Article
- Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.Journal of biomedical science · 2026Review
- Post-Translational Modifications in Cancer-Associated CD8⁺ T-Cell Exhaustion: Mechanisms and Therapeutic Opportunities.International journal of biological sciences · 2026Review
- NSUN2 Promotes Cancer Immune Evasion via Its Moonlighting Function Acting on Metabolic Reprogramming.Cancer communications (London, England) · 2026Article
- Post-translational modifications in CD8Frontiers in immunology · 2026Review
- The dual role of OTUD3 in cancer: mechanisms and therapeutic implications.Cancer cell international · 2025Review
- Immune-related deubiquitylation spectrum of microsatellite stability colorectal cancer reveals USP7 as a potential immunotherapeutic target.Molecular cancer · 2025Article
- USP18 confers protection against allergic asthma by suppressing CCL8 production in alveolar type II epithelial cells.Respiratory research · 2025Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
24 authors at 7 institutions in 4 countries.
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, Wuhan, 430071, China.ORCID http://orcid.org/0000-0002-5352-3441
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, Wuhan, 430071, China.
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, Wuhan, 430071, China.
Xia BuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
Yishuang SunDepartment 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.
Minling GaoDepartment 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.
Bolin XiangDepartment 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.
Wenjun XiongDepartment 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.
Panpan DaiDepartment 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.
Qi MaoDepartment 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.
Xixin XingDepartment 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.
Yingmeng YaoDepartment 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.
Haisheng YuDepartment 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.
Gaoshan XuDepartment 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.
Siqi LiDepartment of Biology, University of Copenhagen, Copenhagen, 2100, Denmark.
Yan RenExperiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Baoxiang ChenDepartment of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Congqing JiangDepartment of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Geng MengCollege of Veterinary Medicine, China Agricultural University, Beijing, 100094, China.ORCID http://orcid.org/0000-0003-3335-2283
Yu-Ru LeeInstitute of Biomedical Sciences, Academia Sinica, Taipei, 115201, Taiwan.ORCID http://orcid.org/0000-0001-6592-6806
Wenyi WeiDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0003-0512-3811
Gordon J FreemanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0002-7210-5616
Conghua XieDepartment 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.ORCID http://orcid.org/0000-0001-6623-9864
Jinfang ZhangDepartment 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.ORCID http://orcid.org/0000-0001-8487-6007
Wuhan University · CNHarvard University · USBeth Israel Deaconess Medical Center · USChina Agricultural University · CNInstitute of Biomedical Sciences, Academia Sinica · TWShanghai University of Traditional Chinese Medicine · CNUniversity of Copenhagen · DK
Funding
Treating the P13-Kinase/AKTP50CA101942 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI Wanling Xie · 2003 to 2026
$53.4MNCI NIH HHS P50 CA101942
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.
Indexed as
Extracellular Signal-Regulated MAP KinasesProgrammed Cell Death 1 ReceptorAnimalsHomeostasisImmunotherapyMiceUbiquitin-Specific ProteasesExtracellular Signal-Regulated MAP KinasesProgrammed Cell Death 1 ReceptorUbiquitin-Specific ProteasesUsp5 protein, mouse
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