Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2
Summary: Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosylation and ubiquitination in regulating PD-1 stability. We show that the removal of N...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723007040 |
| _version_ | 1827915215429173248 |
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| author | Zhen Wu Zhijie Cao Han Yao Xiaojun Yan Wenbin Xu Mi Zhang Zishan Jiao Zijing Zhang Jianyuan Chen Yajing Liu Meng Zhang Donglai Wang |
| author_facet | Zhen Wu Zhijie Cao Han Yao Xiaojun Yan Wenbin Xu Mi Zhang Zishan Jiao Zijing Zhang Jianyuan Chen Yajing Liu Meng Zhang Donglai Wang |
| author_sort | Zhen Wu |
| collection | DOAJ |
| description | Summary: Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosylation and ubiquitination in regulating PD-1 stability. We show that the removal of N-linked glycosylation is a prerequisite for efficient PD-1 ubiquitination and degradation. Murine double minute 2 (MDM2) is identified as an E3 ligase of deglycosylated PD-1. In addition, the presence of MDM2 facilitates glycosylated PD-1 interaction with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Functionally, we demonstrate that the absence of T cell-specific MDM2 accelerates tumor growth by primarily upregulating PD-1. By stimulating the p53-MDM2 axis, interferon-α (IFN-α) reduces PD-1 levels in T cells, which, in turn, exhibit a synergistic effect on tumor suppression by sensitizing anti-PD-1 immunotherapy. Our study reveals that MDM2 directs PD-1 degradation via a deglycosylation-ubiquitination coupled mechanism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis. |
| first_indexed | 2024-03-13T02:56:20Z |
| format | Article |
| id | doaj.art-3ba19516eb4f48598ec8d504849675ad |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T02:56:20Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3ba19516eb4f48598ec8d504849675ad2023-06-28T04:29:27ZengElsevierCell Reports2211-12472023-07-01427112693Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2Zhen Wu0Zhijie Cao1Han Yao2Xiaojun Yan3Wenbin Xu4Mi Zhang5Zishan Jiao6Zijing Zhang7Jianyuan Chen8Yajing Liu9Meng Zhang10Donglai Wang11State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaDepartment of Anatomy, Histology and Embryology, School of Basic Medicine, China Medical University, Shenyang 110122, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, ChinaState Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Corresponding authorSummary: Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosylation and ubiquitination in regulating PD-1 stability. We show that the removal of N-linked glycosylation is a prerequisite for efficient PD-1 ubiquitination and degradation. Murine double minute 2 (MDM2) is identified as an E3 ligase of deglycosylated PD-1. In addition, the presence of MDM2 facilitates glycosylated PD-1 interaction with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Functionally, we demonstrate that the absence of T cell-specific MDM2 accelerates tumor growth by primarily upregulating PD-1. By stimulating the p53-MDM2 axis, interferon-α (IFN-α) reduces PD-1 levels in T cells, which, in turn, exhibit a synergistic effect on tumor suppression by sensitizing anti-PD-1 immunotherapy. Our study reveals that MDM2 directs PD-1 degradation via a deglycosylation-ubiquitination coupled mechanism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis.http://www.sciencedirect.com/science/article/pii/S2211124723007040CP: Molecular biologyCP: Cancer |
| spellingShingle | Zhen Wu Zhijie Cao Han Yao Xiaojun Yan Wenbin Xu Mi Zhang Zishan Jiao Zijing Zhang Jianyuan Chen Yajing Liu Meng Zhang Donglai Wang Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2 Cell Reports CP: Molecular biology CP: Cancer |
| title | Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2 |
| title_full | Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2 |
| title_fullStr | Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2 |
| title_full_unstemmed | Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2 |
| title_short | Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2 |
| title_sort | coupled deglycosylation ubiquitination cascade in regulating pd 1 degradation by mdm2 |
| topic | CP: Molecular biology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723007040 |
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