Gehart Helmuth, Ricci Romeo
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire); INSERM; CNRS; Université de Strasbourg; Illkirch, France ; Institute of Cell Biology; ETH Zurich; Zurich, Switzerland.
Commun Integr Biol. 2013 Mar 1;6(2):e23098. doi: 10.4161/cib.23098.
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?
分泌颗粒的生物发生是激素和神经递质调节性释放的关键过程。一个突出的例子是胰腺β细胞，它分泌胰岛素，胰岛素是一种主要的合成代谢激素，在营养物质可利用时控制细胞代谢。我们最近描述了一种检查点机制，该机制会在反式高尔基体网络（TGN）处阻止新生分泌颗粒的分裂，直到胰岛素完全装载完成。我们证明，含Bin/Amphiphysin/Rvs（BAR）结构域的蛋白Arfaptin-1会阻止颗粒分裂，直到它被蛋白激酶D（PKD）磷酸化。Arfaptin-1的磷酸化会使其与ADP-核糖基化因子（ARF）的结合释放，从而允许分裂发生。β细胞中缺乏这种控制机制会导致过早分裂、产生功能失调的胰岛素颗粒以及受损的调节性胰岛素分泌，而不会影响其他运输载体的组成型释放。在这里，我们讨论与这项工作相关的两个重要问题：PKD如何感知颗粒装载的完成，以及Arfaptin-1如何特异性调节β细胞中胰岛素颗粒的形成？
