Saving the neck from scission.

Secretory granule biogenesis is a pivotal process for regulated release of hormones and neurotransmitters. A prominent example is the pancreatic β cell that secretes insulin, a major anabolic hormone controlling cellular metabolism upon nutrient availability. We recently described a checkpoint mechanism that halts scission of nascent secretory granules at the trans-Golgi network (TGN) until complete loading of insulin is achieved. We demonstrated that the Bin/Amphiphysin/Rvs (BAR) domain-containing protein Arfaptin-1 prevents granule scission until it is phosphorylated by Protein Kinase D (PKD). Arfaptin-1 phosphorylation releases its binding to ADP-rybosylation factor (ARF) allowing scission to occur. Lack of this control mechanism in β cells resulted in premature scission, generation of dysfunctional insulin granules and impaired regulated insulin secretion without affecting constitutive release of other transport carriers. Here we discuss two important questions related to this work: How might completion of granule loading be sensed by PKD, and how does Arfaptin-1 specifically regulate insulin granule formation in beta cells?