The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells
Objective: Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, howeve...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820302258 |
| _version_ | 1818439918897070080 |
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| author | Ilka Wilhelmi Stephan Grunwald Niclas Gimber Oliver Popp Gunnar Dittmar Anup Arumughan Erich E. Wanker Thomas Laeger Jan Schmoranzer Oliver Daumke Annette Schürmann |
| author_facet | Ilka Wilhelmi Stephan Grunwald Niclas Gimber Oliver Popp Gunnar Dittmar Anup Arumughan Erich E. Wanker Thomas Laeger Jan Schmoranzer Oliver Daumke Annette Schürmann |
| author_sort | Ilka Wilhelmi |
| collection | DOAJ |
| description | Objective: Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic β-cells. Methods: A β-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation. Results: The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co-localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from β-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from β-cell-specific Arfrp1 knockout mice. Conclusion: Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting. |
| first_indexed | 2024-12-14T18:04:06Z |
| format | Article |
| id | doaj.art-1448fb0556da4f3e9a968b2dfe04626d |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-14T18:04:06Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-1448fb0556da4f3e9a968b2dfe04626d2022-12-21T22:52:24ZengElsevierMolecular Metabolism2212-87782021-03-0145101151The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cellsIlka Wilhelmi0Stephan Grunwald1Niclas Gimber2Oliver Popp3Gunnar Dittmar4Anup Arumughan5Erich E. Wanker6Thomas Laeger7Jan Schmoranzer8Oliver Daumke9Annette Schürmann10German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD) Munich Neuherberg, GermanyMax-Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, GermanyAdvanced Medical Bioimaging Core Facility – AMBIO, Charité-Universitätsmedizin Berlin, GermanyMax-Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin, GermanyMax-Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin, GermanyNeuroproteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin, GermanyNeuroproteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin, GermanyGerman Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD) Munich Neuherberg, GermanyAdvanced Medical Bioimaging Core Facility – AMBIO, Charité-Universitätsmedizin Berlin, GermanyMax-Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, GermanyGerman Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD) Munich Neuherberg, Germany; University of Potsdam, Institute of Nutritional Sciences, Nuthetal, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus – Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, Germany; Corresponding author. German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Germany.Objective: Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic β-cells. Methods: A β-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation. Results: The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co-localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from β-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from β-cell-specific Arfrp1 knockout mice. Conclusion: Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting.http://www.sciencedirect.com/science/article/pii/S2212877820302258Insulin secretionEndosomal sortingSNARE proteinstrans-Golgi network |
| spellingShingle | Ilka Wilhelmi Stephan Grunwald Niclas Gimber Oliver Popp Gunnar Dittmar Anup Arumughan Erich E. Wanker Thomas Laeger Jan Schmoranzer Oliver Daumke Annette Schürmann The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells Molecular Metabolism Insulin secretion Endosomal sorting SNARE proteins trans-Golgi network |
| title | The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells |
| title_full | The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells |
| title_fullStr | The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells |
| title_full_unstemmed | The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells |
| title_short | The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells |
| title_sort | arfrp1 dependent golgi scaffolding protein gopc is required for insulin secretion from pancreatic β cells |
| topic | Insulin secretion Endosomal sorting SNARE proteins trans-Golgi network |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820302258 |
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