RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells
Objective: A longstanding question in type 1 diabetes (T1D) research pertains to the selective loss of β-cells whilst neighboring islet α-cells remain unharmed. We examined molecular mechanisms that may underly this differential vulnerability, by investigating the role of RNA editing, a cellular pro...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000900 |
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| author | Shani Peleg Liza Zamashanski Jonathan Belin Roy Novoselsky Roni Cohen-Fultheim Udi Ehud Knebel Benjamin Glaser Shalev Itzkovitz Klaus H. Kaestner Alvin C. Powers Erez Y. Levanon Agnes Klochendler Yuval Dor |
| author_facet | Shani Peleg Liza Zamashanski Jonathan Belin Roy Novoselsky Roni Cohen-Fultheim Udi Ehud Knebel Benjamin Glaser Shalev Itzkovitz Klaus H. Kaestner Alvin C. Powers Erez Y. Levanon Agnes Klochendler Yuval Dor |
| author_sort | Shani Peleg |
| collection | DOAJ |
| description | Objective: A longstanding question in type 1 diabetes (T1D) research pertains to the selective loss of β-cells whilst neighboring islet α-cells remain unharmed. We examined molecular mechanisms that may underly this differential vulnerability, by investigating the role of RNA editing, a cellular process that prevents double-stranded RNA (dsRNA)-mediated interferon response, in mouse α- and β-cells. Methods: The enzyme responsible for RNA editing, Adar, was selectively deleted in vivo in mouse β-cells, α-cells, or in both cell types. Subsequent analyses were performed to investigate the impact of deficient RNA editing in α- or β-cells on the interferon response, islet inflammation, cell viability and metabolic outcomes. Results: Mosaic disruption of the Adar gene in mouse β-cells triggers a massive interferon response, islet inflammation and mutant β-cell destruction. Surprisingly, wild type β-cells are also eliminated, whereas neighboring α-cells are unaffected. α-cell Adar deletion leads to only a slight elevation in interferon signature and does not elicit inflammation nor a metabolic phenotype. Concomitant deletion of Adar in α- and β-cells leads to elimination of both cell populations, suggesting that in contrast to β-cells, α-cell death requires both cell autonomous deficiency in RNA editing and exogenous cytokines. Conclusions: We demonstrate differential sensitivity of mouse α- and β-cells to deficient RNA editing. The resistance of α-cells to RNA editing deficiency and to cytokines mirrors their persistence in T1D, and constitutes a molecularly defined model of differential islet cell vulnerability. |
| format | Article |
| id | doaj-art-b39b6cd886c7477b94079fd0f4811d41 |
| institution | DOAJ |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-b39b6cd886c7477b94079fd0f4811d412025-08-20T03:17:24ZengElsevierMolecular Metabolism2212-87782025-08-019810218310.1016/j.molmet.2025.102183RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cellsShani Peleg0Liza Zamashanski1Jonathan Belin2Roy Novoselsky3Roni Cohen-Fultheim4Udi Ehud Knebel5Benjamin Glaser6Shalev Itzkovitz7Klaus H. Kaestner8Alvin C. Powers9Erez Y. Levanon10Agnes Klochendler11Yuval Dor12Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, IsraelThe Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel; Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, IsraelDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, IsraelDepartment of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADivision of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN, 37212, USAThe Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel; Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; Corresponding author.Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; Corresponding author.Objective: A longstanding question in type 1 diabetes (T1D) research pertains to the selective loss of β-cells whilst neighboring islet α-cells remain unharmed. We examined molecular mechanisms that may underly this differential vulnerability, by investigating the role of RNA editing, a cellular process that prevents double-stranded RNA (dsRNA)-mediated interferon response, in mouse α- and β-cells. Methods: The enzyme responsible for RNA editing, Adar, was selectively deleted in vivo in mouse β-cells, α-cells, or in both cell types. Subsequent analyses were performed to investigate the impact of deficient RNA editing in α- or β-cells on the interferon response, islet inflammation, cell viability and metabolic outcomes. Results: Mosaic disruption of the Adar gene in mouse β-cells triggers a massive interferon response, islet inflammation and mutant β-cell destruction. Surprisingly, wild type β-cells are also eliminated, whereas neighboring α-cells are unaffected. α-cell Adar deletion leads to only a slight elevation in interferon signature and does not elicit inflammation nor a metabolic phenotype. Concomitant deletion of Adar in α- and β-cells leads to elimination of both cell populations, suggesting that in contrast to β-cells, α-cell death requires both cell autonomous deficiency in RNA editing and exogenous cytokines. Conclusions: We demonstrate differential sensitivity of mouse α- and β-cells to deficient RNA editing. The resistance of α-cells to RNA editing deficiency and to cytokines mirrors their persistence in T1D, and constitutes a molecularly defined model of differential islet cell vulnerability.http://www.sciencedirect.com/science/article/pii/S2212877825000900RNA editingType 1 diabetesβ-cellsα-cellsIslet inflammationInterferon response |
| spellingShingle | Shani Peleg Liza Zamashanski Jonathan Belin Roy Novoselsky Roni Cohen-Fultheim Udi Ehud Knebel Benjamin Glaser Shalev Itzkovitz Klaus H. Kaestner Alvin C. Powers Erez Y. Levanon Agnes Klochendler Yuval Dor RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells Molecular Metabolism RNA editing Type 1 diabetes β-cells α-cells Islet inflammation Interferon response |
| title | RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells |
| title_full | RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells |
| title_fullStr | RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells |
| title_full_unstemmed | RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells |
| title_short | RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells |
| title_sort | rna editing deficiency models differential immunogenicity of pancreatic α and β cells |
| topic | RNA editing Type 1 diabetes β-cells α-cells Islet inflammation Interferon response |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000900 |
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