Munc 18-1 and granuphilin collaborate during insulin granule exocytosis |
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Authors: | Tomas Alejandra Meda Paolo Regazzi Romano Pessin Jeffrey E Halban Philippe A |
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Affiliation: | Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland; Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1211 Geneva 4, Switzerland; Department of Cell Biology and Morphology, University of Lausanne, 1005 Lausanne, Switzerland; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA |
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Abstract: | Munc 18-1 is a member of the Sec/Munc family of syntaxin-binding proteins known to bind to the plasma membrane Q-SNARE syntaxin1 and whose precise role in regulated exocytosis remains controversial. Here, we show that Munc 18-1 plays a positive role in regulated insulin secretion from pancreatic beta cells. Munc 18-1 depletion caused a loss in the secretory capacity of both transiently transfected INS 1E cells and a stable clone with tetracycline-regulated Munc 18-1 RNA interference. In addition, Munc 18-1-depleted cells exhibited defective docking of insulin granules to the plasma membrane and accumulated insulin in the trans Golgi network. Furthermore, glucose stimulation after Munc 18-1 depletion resulted in the rapid formation of autophagosomes. In contrast, overexpression of Munc 18-1 had no effect on insulin secretion. Although there was no detectable interaction between Munc 18-1 and Munc-18-interacting protein 1 or calcium/calmodulin-dependent serine protein kinase, Munc 18-1 associated with the granular protein granuphilin. This association was regulated by glucose and was required for the specific interaction of insulin granules with syntaxin1. We conclude that Munc 18-1 and granuphilin collaborate in the docking of insulin granules to the plasma membrane in an initial fusion-incompetent state, with Munc 18-1 subsequently playing a positive role in a later stage of insulin granule exocytosis. |
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Keywords: | autophagy docking granuphilin insulin granule Munc 18-1 trans Golgi network |
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