The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells
Open accessAbstract
Background: Many cancers evade immune surveillance by overexpressing PD-L1. PD-L1 interacted with its receptor PD-1, resulting in reduction of T cell proliferation and activation and thereafter cancer cell death mediated by T-lymphocyte. Understanding the mechanisms that regulate PD-L1 was of vital importance for immune checkpoint blockade therapy (ICBT). Methods: Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of USP22 upon PD-L1 and CSN5 by WB, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. B16-F10 cells were used to explore the role of USP22 on tumorigenesis and T cell cytotoxicity. The relationship between USP22 and PD-L1 expression was investigated by Immunohistochemistry analysis in human non-small cell lung cancer samples. Results: Our data showed that USP22 interacted with PD-L1 and promoted its stability. USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation. Moreover, USP22 also interacted with CSN5 and stabilized CSN5 through deubiquitination. Either USP22 or CSN5 could facilitate the interaction of PD-L1 with the other one. Furthermore, USP22 removed K6, K11, K27, K29, K33 and K63-linked ubiquitin chain of both CSN5 and PD-L1. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Conclusions: Here, we suggested that USP22 is a new regulator for PD-L1. On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination. On the other hand, USP22 regulated PD-L1 protein level through USP22-CSN5-PD-L1 axis. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Together, we identified a new regulator of PD-L1 and characterized the important role of USP22 in PD-L1 mediated immune evasion. Targeting USP22 might be a new solution to ICBT. Graphical abstract:
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A recent study revealed that USP22 could regulate PD-L1 expression in a direct and indirect way.
“Supporting this view, a recent study revealed that USP22 could regulate PD-L1 expression in a direct and indirect way37.”
From PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells (2022) · cites this paper as [37]
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References 60 · Cited by 124
- Authors
- Wang, Y., Sun, Q., Mu, N., Sun, X., Wang, Y., Fan, S., Su, L., & Liu, X.
- Affiliations
- Shandong University (CN)
- Second Xiangya Hospital of Central South University (CN)
- Corresponding author
- Su, Ling
- Liu, Xiangguo
- Venue
- Cell Communication and Signaling
- Published
- 2020-07-14
- Volume
- 18
- Issue
- 1
- Pages
- 112-112
- ISSN
- 1478-811X (ISSN-L)
- PMC
- PMC7362500
- OpenAlex
- W3043427197
- Cited by
- 124
- References
- 60
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 26 · 2023: 22 · 2022: 19 · 2021: 17 · 2020: 2
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Communication and Signaling (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81672855, 31771526, 81773218)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- USP22, PD-L1, deubiquitination, protein stability, CSN5, proteasomal degradation, immune checkpoint blockade, tumor immune evasion, non-small cell lung cancer, T cell cytotoxicity, ubiquitin chains, carcinogenesis
- MeSH terms
- COP9 Signalosome Complex, Animals, Carcinoma, Non-Small-Cell Lung, Cytotoxicity, Immunologic, Humans, Immunosuppression Therapy, Lung Neoplasms, Peptide Hydrolases, Protein Binding, T-Lymphocytes, Ubiquitin Thiolesterase, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, Ubiquitination, Protein Stability, HEK293 Cells, Proteolysis, B7-H1 Antigen, Carcinogenesis
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