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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。

An early endosome-derived retrograde trafficking pathway promotes secretory granule maturation.

机构信息

Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

出版信息

J Cell Biol. 2020 Mar 2;219(3). doi: 10.1083/jcb.201808017.

DOI:10.1083/jcb.201808017
PMID:32045479
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7055004/
Abstract

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.

摘要

受调控的分泌是一种基本的细胞过程，其中储存在持久的分泌颗粒 (SGs) 中的生物活性分子会响应外部刺激而被分泌。许多研究已经描述了负责 SG 生物发生和分泌的机制，但 SG 如何成熟仍然知之甚少。在一项遗传筛选中，我们发现了大量内体运输基因对于 SG 成熟是必需的，这表明 SG 的成熟可能以类似于溶酶体相关细胞器 (LROs) 的方式发生。CD63，一种已知装饰 LRO 的四跨膜蛋白，也装饰 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) 依赖性早期内体分选和 SG 膜上磷酸肌醇 4-磷酸 (PI4P) 的积累。此外，PI4P 效应因子 Past1 对于与该过程相关的稳定含有 PI4KII 的内体小管的形成是必需的。我们的结果表明，高尔基后衍生的 SG 的成熟需要通过内体系统进行运输，类似于 LROs 所采用的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/7d374928f07f/JCB_201808017_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/868fb62b8523/JCB_201808017_Fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/984a3cfcd60c/JCB_201808017_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/c49eb6dd8092/JCB_201808017_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/71a487b26922/JCB_201808017_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/618f0cf7d1dd/JCB_201808017_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/43d1fd792937/JCB_201808017_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/8070ad3795de/JCB_201808017_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/f471b0054e2d/JCB_201808017_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/7f76173aa2f5/JCB_201808017_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/b2dc7f430b89/JCB_201808017_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/7d374928f07f/JCB_201808017_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/868fb62b8523/JCB_201808017_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/64e07630d465/JCB_201808017_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/984a3cfcd60c/JCB_201808017_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/c49eb6dd8092/JCB_201808017_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/71a487b26922/JCB_201808017_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/618f0cf7d1dd/JCB_201808017_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/43d1fd792937/JCB_201808017_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/8070ad3795de/JCB_201808017_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/f471b0054e2d/JCB_201808017_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/7f76173aa2f5/JCB_201808017_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/b2dc7f430b89/JCB_201808017_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0825/7055004/7d374928f07f/JCB_201808017_Fig8.jpg

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