Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation
Abstract Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-34346-x |
| _version_ | 1826932668770549760 |
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| author | Chengyu Shi Ying Wang Minjie Wu Yu Chen Fangzhou Liu Zheyuan Shen Yiran Wang Shaofang Xie Yingying Shen Lingjie Sang Zhen Zhang Zerui Gao Luojia Yang Lei Qu Zuozhen Yang Xinyu He Yu Guo Chenghao Pan Jinxin Che Huaiqiang Ju Jian Liu Zhijian Cai Qingfeng Yan Luyang Yu Liangjing Wang Xiaowu Dong Pinglong Xu Jianzhong Shao Yang Liu Xu Li Wenqi Wang Ruhong Zhou Tianhua Zhou Aifu Lin |
| author_facet | Chengyu Shi Ying Wang Minjie Wu Yu Chen Fangzhou Liu Zheyuan Shen Yiran Wang Shaofang Xie Yingying Shen Lingjie Sang Zhen Zhang Zerui Gao Luojia Yang Lei Qu Zuozhen Yang Xinyu He Yu Guo Chenghao Pan Jinxin Che Huaiqiang Ju Jian Liu Zhijian Cai Qingfeng Yan Luyang Yu Liangjing Wang Xiaowu Dong Pinglong Xu Jianzhong Shao Yang Liu Xu Li Wenqi Wang Ruhong Zhou Tianhua Zhou Aifu Lin |
| author_sort | Chengyu Shi |
| collection | DOAJ |
| description | Abstract Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target. |
| first_indexed | 2024-04-11T06:55:42Z |
| format | Article |
| id | doaj.art-5c9afa68434c4156b9404910dc8406e1 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2025-02-17T17:18:08Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5c9afa68434c4156b9404910dc8406e12024-12-15T12:09:56ZengNature PortfolioNature Communications2041-17232022-11-0113111810.1038/s41467-022-34346-xPromoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylationChengyu Shi0Ying Wang1Minjie Wu2Yu Chen3Fangzhou Liu4Zheyuan Shen5Yiran Wang6Shaofang Xie7Yingying Shen8Lingjie Sang9Zhen Zhang10Zerui Gao11Luojia Yang12Lei Qu13Zuozhen Yang14Xinyu He15Yu Guo16Chenghao Pan17Jinxin Che18Huaiqiang Ju19Jian Liu20Zhijian Cai21Qingfeng Yan22Luyang Yu23Liangjing Wang24Xiaowu Dong25Pinglong Xu26Jianzhong Shao27Yang Liu28Xu Li29Wenqi Wang30Ruhong Zhou31Tianhua Zhou32Aifu Lin33MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityInnovation Institute for Artificial Intelligence in Medicine, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityKey Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake UniversityInstitute of Immunology, Zhejiang University School of MedicineMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityHangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang UniversityInnovation Institute for Artificial Intelligence in Medicine, Zhejiang UniversityHangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang UniversitySun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineZhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang UniversityInstitute of Immunology, Zhejiang University School of MedicineMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityDepartment of Gastroenterology, the Second Affiliated Hospital, School of Medicine and Institute of Gastroenterology, Zhejiang UniversityInnovation Institute for Artificial Intelligence in Medicine, Zhejiang UniversityMOE Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityInstitute of Immunology, Zhejiang University School of MedicineKey Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake UniversityDepartment of Developmental and Cell Biology, University of CaliforniaMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityCancer Center, Zhejiang UniversityMOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang UniversityAbstract Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.https://doi.org/10.1038/s41467-022-34346-x |
| spellingShingle | Chengyu Shi Ying Wang Minjie Wu Yu Chen Fangzhou Liu Zheyuan Shen Yiran Wang Shaofang Xie Yingying Shen Lingjie Sang Zhen Zhang Zerui Gao Luojia Yang Lei Qu Zuozhen Yang Xinyu He Yu Guo Chenghao Pan Jinxin Che Huaiqiang Ju Jian Liu Zhijian Cai Qingfeng Yan Luyang Yu Liangjing Wang Xiaowu Dong Pinglong Xu Jianzhong Shao Yang Liu Xu Li Wenqi Wang Ruhong Zhou Tianhua Zhou Aifu Lin Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation Nature Communications |
| title | Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation |
| title_full | Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation |
| title_fullStr | Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation |
| title_full_unstemmed | Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation |
| title_short | Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation |
| title_sort | promoting anti tumor immunity by targeting tmub1 to modulate pd l1 polyubiquitination and glycosylation |
| url | https://doi.org/10.1038/s41467-022-34346-x |
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