USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation
Abstract The N6-methyladenosine binding protein YTHDF1, often upregulated in cancer, promotes tumor growth and hinders immune checkpoint blockade treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates a...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56564-9 |
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| author | Na Shao Lei Xi Yangfan Lv Muhammad Idris Lin Zhang Ya Cao Jingyi Xiang Xi Xu Belinda X. Ong Qiongyi Zhang Xu Peng Xiaoyan Yue Feng Xu Chungang Liu |
| author_facet | Na Shao Lei Xi Yangfan Lv Muhammad Idris Lin Zhang Ya Cao Jingyi Xiang Xi Xu Belinda X. Ong Qiongyi Zhang Xu Peng Xiaoyan Yue Feng Xu Chungang Liu |
| author_sort | Na Shao |
| collection | DOAJ |
| description | Abstract The N6-methyladenosine binding protein YTHDF1, often upregulated in cancer, promotes tumor growth and hinders immune checkpoint blockade treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of immune checkpoint blockade in cancer patients. Here, we report that USP5 interacts with YTHDF1, stabilizing it by removing K11-linked polyubiquitination. Insulin activates mTORC1, phosphorylating USP5 and promoting its dimerization, which binds to and protects YTHDF1 from degradation. Conversely, the CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation. Deficiency in YTHDF1 or USP5 increases PD-L1 expression and suppresses immune-related gene expression, facilitating immune evasion. Combining USP5 inhibition with anti-PD-L1 therapy enhances anti-tumor immunity, suggesting USP5 as a potential biomarker for patient stratification. This study reveals a ubiquitination-dependent regulation of YTHDF1, proposing USP5 inhibition alongside PD-(L)1 blockade as a promising cancer treatment strategy. |
| format | Article |
| id | doaj-art-b33de7d8fcaa481c9c10ad4eb7c98080 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b33de7d8fcaa481c9c10ad4eb7c980802025-02-09T12:43:57ZengNature PortfolioNature Communications2041-17232025-02-0116111810.1038/s41467-025-56564-9USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylationNa Shao0Lei Xi1Yangfan Lv2Muhammad Idris3Lin Zhang4Ya Cao5Jingyi Xiang6Xi Xu7Belinda X. Ong8Qiongyi Zhang9Xu Peng10Xiaoyan Yue11Feng Xu12Chungang Liu13Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical UniversityCollege of Biological and Food Engineering, Hubei Minzu UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Pathology, Second Affiliated Hospital, Zhejiang University School of MedicineInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical UniversityAbstract The N6-methyladenosine binding protein YTHDF1, often upregulated in cancer, promotes tumor growth and hinders immune checkpoint blockade treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of immune checkpoint blockade in cancer patients. Here, we report that USP5 interacts with YTHDF1, stabilizing it by removing K11-linked polyubiquitination. Insulin activates mTORC1, phosphorylating USP5 and promoting its dimerization, which binds to and protects YTHDF1 from degradation. Conversely, the CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation. Deficiency in YTHDF1 or USP5 increases PD-L1 expression and suppresses immune-related gene expression, facilitating immune evasion. Combining USP5 inhibition with anti-PD-L1 therapy enhances anti-tumor immunity, suggesting USP5 as a potential biomarker for patient stratification. This study reveals a ubiquitination-dependent regulation of YTHDF1, proposing USP5 inhibition alongside PD-(L)1 blockade as a promising cancer treatment strategy.https://doi.org/10.1038/s41467-025-56564-9 |
| spellingShingle | Na Shao Lei Xi Yangfan Lv Muhammad Idris Lin Zhang Ya Cao Jingyi Xiang Xi Xu Belinda X. Ong Qiongyi Zhang Xu Peng Xiaoyan Yue Feng Xu Chungang Liu USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation Nature Communications |
| title | USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation |
| title_full | USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation |
| title_fullStr | USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation |
| title_full_unstemmed | USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation |
| title_short | USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation |
| title_sort | usp5 stabilizes ythdf1 to control cancer immune surveillance through mtorc1 mediated phosphorylation |
| url | https://doi.org/10.1038/s41467-025-56564-9 |
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