The BAR Domain Protein Arfaptin-1 Controls Secretory Granule Biogenesis at the trans-Golgi Network

摘要

BAR domains can prevent membrane fission through their ability to shield necks of budding vesicles from fission-inducing factors. However, the physiological role of this inhibitory function and its regulation is unknown. Here we identify a checkpoint involving the BAR-domain-containing protein Arfaptin-1 that controls biogenesis of secretory granules at the trans-Golgi network (TGN). We demonstrate that protein kinase D (PKD) phosphorylates Arfaptin-1 at serine 132, which disrupts the ability of Arfaptin-1 to inhibit the activity of ADP ribosylation factor, an important component of the vesicle scission machinery. The physiological significance of this regulatory mechanism is evidenced by loss of glucose-stimulated insulin secretion due to granule scission defects in pancreatic β cells expressing nonphosphorylatable Arfaptin-1. Accordingly, depletion of Arfaptin-1 leads to the generation of small nonfunctional secretory granules. Hence, PKD-mediated Arfaptin-1 phosphorylation is necessary to ensure biogenesis of functional transport carriers at the TGN in regulated secretion. Tight regulation of membrane scission at the Golgi is essential for generation of properly loaded secretory vesicles. Gehart et al. report a checkpoint mechanism in pancreatic beta cells mediated by BAR-domain-containing Arfaptin-1. This mechanism allows PKD signaling to activate membrane scission of insulin granules, coordinating glucose-stimulated insulin secretion.