Deubiquitination and Stabilization of PD-L1 by CSN5
Open accessAbstract
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.
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Several critical proteins including CMTM4, CMTM6, GSK3β, CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability.
“Moreover, several critical proteins including CMTM4, CMTM6, GSK3β, CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability31–36.”
From PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells (2022) · cites this paper as [35]
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Self-citation
- Authors
- Lim, S.-O., Li, C.-W., Xia, W., Cha, J.-H., Chan, L.-C., Wu, Y., Chang, S.-S., Lin, W.-C., Hsu, J.-M., Hsu, Y.-H., Kim, T., Chang, W.-C., Hsu, J. L., Yamaguchi, H., Ding, Q., Wang, Y., Yang, Y., Chen, C.-H., Sahin, A. A., Yu, D., Hortobagyi, G. N., & Hung, M.-C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- China Medical University (TW)
- Genomics Research Center, Academia Sinica (TW)
- Corresponding author
- Hung, Mien-Chie
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 30
- Issue
- 6
- Pages
- 925-939
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5171205
- OpenAlex
- W2554320328
- Cited by
- 793
- References
- 43
- Citations by year
- 2026: 68 · 2025: 81 · 2024: 106 · 2023: 109 · 2022: 90 · 2021: 111 · 2020: 97 · 2019: 48 · 2018: 55 · 2017: 27 · 2016: 1
- FWCI
- 23.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA109311, CA099031, CA016672)
- Cancer Prevention Research Institute of Texas (RP160710)
- Patel Memorial Breast Cancer Endowment Fund
- National Breast Cancer Foundation
- Breast Cancer Research Foundation
- University of Texas MD Anderson Cancer Center
- China Medical University
- Hospital Sister Institution Fund
- Ministry of Science and Technology (105-2911-I-002-302)
- International Research-intensive Centers of Excellence
- Ministry of Health and Welfare (MOHW105-TDU-B-212-134003)
- Center for Biological Pathways
- Cure Postdoctoral Fellowship (PDF12231298)
- National Research Foundation of Korea (NRF-2011-357-C00140, 2011-0030001)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PD-L1, CSN5, COP9 signalosome, deubiquitination, protein stabilization, TNF-α, NF-κB p65, tumor immunosuppression, curcumin, CTLA-4 blockade, tumor microenvironment, tumor cell survival
- MeSH terms
- COP9 Signalosome Complex, Animals, Curcumin, Female, Humans, Neoplasm Transplantation, Neoplasms, Peptide Hydrolases, Tumor Necrosis Factor-alpha, NF-kappa B, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, Ubiquitination, Protein Stability, B7-H1 Antigen
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