Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2
Abstract Efficacy of radiation therapy is compromised by hematopoietic and immune impairments, with elusive underlying causes. This study aimed to elucidate Usp11’s role in radiation-induced injuries and uncover related mechanisms. Utilized ARS mouse model to observe survival rates of Usp11−/− (KO)...
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07377-7 |
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| author | Jiaqi Sheng Depei Wu Jingzhe Shang Xiaodan Fu He Gao Jianjie Rong Jun Wang Jiancheng Hu Xiaofei Qi |
| author_facet | Jiaqi Sheng Depei Wu Jingzhe Shang Xiaodan Fu He Gao Jianjie Rong Jun Wang Jiancheng Hu Xiaofei Qi |
| author_sort | Jiaqi Sheng |
| collection | DOAJ |
| description | Abstract Efficacy of radiation therapy is compromised by hematopoietic and immune impairments, with elusive underlying causes. This study aimed to elucidate Usp11’s role in radiation-induced injuries and uncover related mechanisms. Utilized ARS mouse model to observe survival rates of Usp11−/− (KO) mice post-TBI (Total Body Irradiation). Assessed lymphocyte and MZ B (Marginal Zone B) cell rates using histological analysis, single-cell sequencing, immunofluorescence (IF), immunohistochemistry (IHC), and flow cytometry (FCM). Conducted Co-IP and ubiquitination experiments for mechanism elucidation. Quantified IgM and IgG using ELISA and FC. Explored public databases for potential correlation molecules. Our findings indicated that Usp11−/− mice exhibited improved survival rates following TBI, with the spleen playing a pivotal role. HE staining revealed a wider marginal zone in the spleen of Usp11+/+ mice post-irradiation. Single-cell sequencing, IF, IHC, and FCM analyses revealed a higher survival rate of MZ B cells in Usp11−/− mice after irradiation. Furthermore, treatment with the Usp11 inhibitor, mitoxantrone, successfully targeted and inhibited Usp11, thereby alleviating the reduction in MZ B cells in the spleen following total body irradiation. Mechanistically, Usp11 sustained the survival of MZ B cells by regulating the ubiquitination of Notch’s ligands, DLL1 and JAG2, thereby promoting immune cell remodeling in the spleen. In conclusion, Usp11 played a crucial role in modulating immune system damage induced by ionizing radiation, primarily through ubiquitination of Notch ligands. This study provides insights into radiation-induced immune injuries and suggests Usp11 as a potential therapeutic target. |
| format | Article |
| id | doaj-art-b918463a2b434d3cb32ef6c382601452 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-b918463a2b434d3cb32ef6c3826014522025-02-09T12:56:53ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111210.1038/s41419-025-07377-7Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2Jiaqi Sheng0Depei Wu1Jingzhe Shang2Xiaodan Fu3He Gao4Jianjie Rong5Jun Wang6Jiancheng Hu7Xiaofei Qi8Department of Hematology, the First Affiliated Hospital of Soochow University & State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow UniversityDepartment of Hematology, the First Affiliated Hospital of Soochow University & State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow UniversityState Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Hematology, the First Affiliated Hospital of Soochow University & State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow UniversityInstitutes of Biology and Medical Sciences, Suzhou Medical College of Soochow UniversityDepartment of Vascular Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese MedicineInstitutes of Biology and Medical Sciences, Suzhou Medical College of Soochow UniversityLaboratory of Molecular Mechanism & Targeted Therapy, National Cancer Center Singapore, Singapore General Hospital, Duke-NUS Medical SchoolDepartment of Hematology, the First Affiliated Hospital of Soochow University & State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow UniversityAbstract Efficacy of radiation therapy is compromised by hematopoietic and immune impairments, with elusive underlying causes. This study aimed to elucidate Usp11’s role in radiation-induced injuries and uncover related mechanisms. Utilized ARS mouse model to observe survival rates of Usp11−/− (KO) mice post-TBI (Total Body Irradiation). Assessed lymphocyte and MZ B (Marginal Zone B) cell rates using histological analysis, single-cell sequencing, immunofluorescence (IF), immunohistochemistry (IHC), and flow cytometry (FCM). Conducted Co-IP and ubiquitination experiments for mechanism elucidation. Quantified IgM and IgG using ELISA and FC. Explored public databases for potential correlation molecules. Our findings indicated that Usp11−/− mice exhibited improved survival rates following TBI, with the spleen playing a pivotal role. HE staining revealed a wider marginal zone in the spleen of Usp11+/+ mice post-irradiation. Single-cell sequencing, IF, IHC, and FCM analyses revealed a higher survival rate of MZ B cells in Usp11−/− mice after irradiation. Furthermore, treatment with the Usp11 inhibitor, mitoxantrone, successfully targeted and inhibited Usp11, thereby alleviating the reduction in MZ B cells in the spleen following total body irradiation. Mechanistically, Usp11 sustained the survival of MZ B cells by regulating the ubiquitination of Notch’s ligands, DLL1 and JAG2, thereby promoting immune cell remodeling in the spleen. In conclusion, Usp11 played a crucial role in modulating immune system damage induced by ionizing radiation, primarily through ubiquitination of Notch ligands. This study provides insights into radiation-induced immune injuries and suggests Usp11 as a potential therapeutic target.https://doi.org/10.1038/s41419-025-07377-7 |
| spellingShingle | Jiaqi Sheng Depei Wu Jingzhe Shang Xiaodan Fu He Gao Jianjie Rong Jun Wang Jiancheng Hu Xiaofei Qi Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2 Cell Death and Disease |
| title | Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2 |
| title_full | Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2 |
| title_fullStr | Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2 |
| title_full_unstemmed | Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2 |
| title_short | Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2 |
| title_sort | usp11 maintained the survival of marginal zone b cells under ionizing radiation by deubiquitinating dll1 and jag2 |
| url | https://doi.org/10.1038/s41419-025-07377-7 |
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