Department of Medicine, University of California San Diego, La Jolla, California 92093-0838.
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838.
J Biol Chem. 2010 Mar 26;285(13):10030-10043. doi: 10.1074/jbc.M109.064196. Epub 2010 Jan 8.
Processes underlying the formation of dense core secretory granules (DCGs) of neuroendocrine cells are poorly understood. Here, we present evidence that DCG biogenesis is dependent on the secretory protein secretogranin (Sg) II, a member of the granin family of pro-hormone cargo of DCGs in neuroendocrine cells. Depletion of SgII expression in PC12 cells leads to a decrease in both the number and size of DCGs and impairs DCG trafficking of other regulated hormones. Expression of SgII fusion proteins in a secretory-deficient PC12 variant rescues a regulated secretory pathway. SgII-containing dense core vesicles share morphological and physical properties with bona fide DCGs, are competent for regulated exocytosis, and maintain an acidic luminal pH through the V-type H(+)-translocating ATPase. The granulogenic activity of SgII requires a pH gradient along this secretory pathway. We conclude that SgII is a critical factor for the regulation of DCG biogenesis in neuroendocrine cells, mediating the formation of functional DCGs via its pH-dependent aggregation at the trans-Golgi network.
神经内分泌细胞致密核心分泌颗粒 (DCGs) 的形成过程尚不清楚。本文提供的证据表明，DCG 的生物发生依赖于分泌蛋白 SgII，它是 DCGs 中激素前体货物颗粒结合蛋白家族的成员。PC12 细胞中 SgII 表达的缺失导致 DCG 的数量和大小减少，并损害其他受调控激素的 DCG 转运。在分泌缺陷型 PC12 变体中表达 SgII 融合蛋白可挽救受调控的分泌途径。含有 SgII 的致密核心囊泡与真正的 DCGs 具有形态和物理特性，有能力进行受调控的胞吐作用，并通过 V 型 H(+)-转运 ATP 酶保持酸性腔室 pH 值。SgII 的成粒活性需要沿着这条分泌途径存在 pH 梯度。我们得出结论，SgII 是神经内分泌细胞中 DCG 生物发生调节的关键因素，通过在高尔基网络中的 pH 依赖性聚集来介导功能性 DCG 的形成。
