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| Item Type: | Article |
|---|---|
| Title: | The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells |
| Creators Name: | Wilhelmi, Ilka and Grunwald, S. and Gimber, N. and Popp, O. and Dittmar, G. and Arumughan, A. and Wanker, E.E. and Laeger, T. and Schmoranzer, J. and Daumke, O. and Schümann, A. |
| Abstract: | 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. Pull down 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. Down-regulation 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. |
| Keywords: | Insulin Secretion, Endosomal Sorting, SNARE Proteins, Trans-Golgi Network, Animals, Mice |
| Source: | Molecular Metabolism |
| ISSN: | 2212-8778 |
| Publisher: | Elsevier |
| Volume: | 45 |
| Page Range: | 101151 |
| Date: | March 2021 |
| Official Publication: | https://doi.org/10.1016/j.molmet.2020.101151 |
| PubMed: | View item in PubMed |
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