2. Academic Validation
  3. Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2

Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2

  • Cell Death Dis. 2025 Feb 4;16(1):67. doi: 10.1038/s41419-025-07377-7.
Jiaqi Sheng # 1 2 3,  Depei Wu # 1 2 3,  Jingzhe Shang # 4,  Xiaodan Fu # 1 2 3,  He Gao 5,  Jianjie Rong 6,  Jun Wang 7,  Jiancheng Hu 8,  Xiaofei Qi 9 10 11
Affiliations

Affiliations

  • 1 Department of Hematology, the First Affiliated Hospital of Soochow University & State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, 215000, China.
  • 2 National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou, 215006, China.
  • 3 Cyrus Tang Hematology Center & Institute of Blood and Marrow Transplantation, Suzhou, 215006, PR China.
  • 4 State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, China.
  • 5 Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
  • 6 Department of Vascular Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215000, China.
  • 7 Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, 215123, China. jwang79@suda.edu.cn.
  • 8 Laboratory of Molecular Mechanism & Targeted Therapy, National Cancer Center Singapore, Singapore General Hospital, Duke-NUS Medical School, Singapore, 168583, Singapore. jiancheng.hu@duke-nus.edu.sg.
  • 9 Department of Hematology, the First Affiliated Hospital of Soochow University & State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, 215000, China. qixf-sz@hotmail.com.
  • 10 National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou, 215006, China. qixf-sz@hotmail.com.
  • 11 Cyrus Tang Hematology Center & Institute of Blood and Marrow Transplantation, Suzhou, 215006, PR China. qixf-sz@hotmail.com.
  • # Contributed equally.
PMID: 39904982 DOI: 10.1038/s41419-025-07377-7
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.

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