Regulated secretion is a fundamental cellular process in which biologically active molecules stored in long-lasting secretory granules (SGs) are secreted in response to external stimuli. Many studies have described mechanisms responsible for biogenesis and secretion of SGs, but how SGs mature remains poorly understood. In a genetic screen, we discovered a large number of endolysosomal trafficking genes required for proper SG maturation, indicating that maturation of SGs might occur in a manner similar to lysosome-related organelles (LROs). CD63, a tetraspanin known to decorate LROs, also decorates SG membranes and facilitates SG maturation. Moreover, CD63-mediated SG maturation requires type II phosphatidylinositol 4 kinase (PI4KII)-dependent early endosomal sorting and accumulation of phosphatidylinositol 4-phosphate (PI4P) on SG membranes. In addition, the PI4P effector Past1 is needed for formation of stable PI4KII-containing endosomal tubules associated with this process. Our results reveal that maturation of post-Golgi–derived SGs requires trafficking via the endosomal system, similar to mechanisms employed by LROs.

中文翻译：

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早期内体衍生的逆行运输途径促进分泌颗粒成熟

调节分泌是一个基本的细胞过程，其中储存在长效分泌颗粒（SG）中的生物活性分子响应外部刺激而被分泌。许多研究已经描述了 SG 的生物发生和分泌机制，但 SG 的成熟机制仍然知之甚少。在遗传筛选中，我们发现了 SG 适当成熟所需的大量内溶酶体运输基因，表明 SG 的成熟可能以类似于溶酶体相关细胞器 (LRO) 的方式发生。CD63 是一种已知可装饰 LRO 的四跨膜蛋白，也可装饰 SG 膜并促进 SG 成熟。此外，CD63介导的SG成熟需要II型磷脂酰肌醇4激酶（PI4KII）依赖性的早期内体分选和磷脂酰肌醇4-磷酸（PI4P）在SG膜上的积累。此外，与此过程相关的稳定的包含 PI4KII 的内体小管的形成需要 PI4P 效应器 Past1。我们的结果表明，后高尔基体衍生的 SG 的成熟需要通过内体系统进行运输，类似于 LRO 所采用的机制。