E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells
T lymphocytes consist of αβ and γδ T cells, which mature and differentiate from the same progenitor cells in the thymus. Cullin-RING ligases (CRLs), the largest family of ubiquitin ligases, require neddylation on the scaffold protein Cullins for their ligase activity. The role of neddylation–CRL sys...
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0774 |
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| author | Di Wu Qiuxu Chen Mingjia Tan Yi Sun |
| author_facet | Di Wu Qiuxu Chen Mingjia Tan Yi Sun |
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| description | T lymphocytes consist of αβ and γδ T cells, which mature and differentiate from the same progenitor cells in the thymus. Cullin-RING ligases (CRLs), the largest family of ubiquitin ligases, require neddylation on the scaffold protein Cullins for their ligase activity. The role of neddylation–CRL system in thymus development and fate determination of αβ/γδ T cells remains elusive. Here, we generated conditional knockout mouse models with thymus individual deletion of Ube2m or Ube2f, 2 neddylation E2-conjugating enzymes, and Rbx1 or Sag, 2 dual neddylation and ubiquitylation E3 ligases. We found that only Rbx1, but not Ube2m/Ube2f, nor Sag, plays an essential role in thymus development and fate determination of αβ/γδ T cells. Specifically, Rbx1 loss causes shrinkage of the thymus, delayed T cell development, increased γδ T cells in the thymus, increased the ratio of immature Gzma+ γδ T cells, and decreased the ratio of the proliferative subpopulation. Some of these phenotypes were moderately rescued by simultaneous Bim deletion. Mechanistically, Rbx1 loss alters the Akt, NF-κB, and metabolic pathways in progenitor γδ T cells/DN3a cells. Finally, Rbx1 loss altered the γδ T1/T17 cell population in the thymus, suggesting that Rbx1 controls the fate of γδ T cells. |
| format | Article |
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| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
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| spelling | doaj-art-d338a80b063b4e2c88c6d09d50f2666c2025-07-10T08:00:18ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0774E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T CellsDi Wu0Qiuxu Chen1Mingjia Tan2Yi Sun3Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.T lymphocytes consist of αβ and γδ T cells, which mature and differentiate from the same progenitor cells in the thymus. Cullin-RING ligases (CRLs), the largest family of ubiquitin ligases, require neddylation on the scaffold protein Cullins for their ligase activity. The role of neddylation–CRL system in thymus development and fate determination of αβ/γδ T cells remains elusive. Here, we generated conditional knockout mouse models with thymus individual deletion of Ube2m or Ube2f, 2 neddylation E2-conjugating enzymes, and Rbx1 or Sag, 2 dual neddylation and ubiquitylation E3 ligases. We found that only Rbx1, but not Ube2m/Ube2f, nor Sag, plays an essential role in thymus development and fate determination of αβ/γδ T cells. Specifically, Rbx1 loss causes shrinkage of the thymus, delayed T cell development, increased γδ T cells in the thymus, increased the ratio of immature Gzma+ γδ T cells, and decreased the ratio of the proliferative subpopulation. Some of these phenotypes were moderately rescued by simultaneous Bim deletion. Mechanistically, Rbx1 loss alters the Akt, NF-κB, and metabolic pathways in progenitor γδ T cells/DN3a cells. Finally, Rbx1 loss altered the γδ T1/T17 cell population in the thymus, suggesting that Rbx1 controls the fate of γδ T cells.https://spj.science.org/doi/10.34133/research.0774 |
| spellingShingle | Di Wu Qiuxu Chen Mingjia Tan Yi Sun E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells Research |
| title | E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells |
| title_full | E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells |
| title_fullStr | E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells |
| title_full_unstemmed | E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells |
| title_short | E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells |
| title_sort | e3 ligase rbx1 orchestrates thymus development and fate determination of αβ γδ t cells |
| url | https://spj.science.org/doi/10.34133/research.0774 |
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