TY - JOUR
A1 - Wilhelmi, Ilka
A1 - Grunwald, Stephan
A1 - Gimber, Niclas
A1 - Popp, Oliver
A1 - Dittmar, Gunnar
A1 - Arumughan, Anup
A1 - Wanker, Erich E.
A1 - Laeger, Thomas
A1 - Schmoranzer, Jan
A1 - Daumke, Oliver
A1 - Schürmann, Annette
T1 - The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic 13-cells
T2 - Molecular metabolism
N2 - 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 13-cells.
Methods: A 13-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 13-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from 13-cell-specific Arfrp1 knockout mice.
Conclusion: Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting. (c) 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
KW - Insulin secretion
KW - Endosomal sorting
KW - SNARE proteins
KW - trans-Golgi
KW - network
Y1 - 2020
UR - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/56418
SN - 2212-8778
VL - 45
PB - Elsevier
CY - Amsterdam
ER -