Distinct linkage between post-translational processing and differential secretion of progastrin derivatives in endocrine cells
Distinct linkage between post-translational processing and differential secretion of progastrin derivatives in endocrine cells
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DOI：
10.1074/jbc.m707908200
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发表时间：
2008-02-15
影响因子：
4.8
通讯作者：
Rehfeld, Jens F.
中科院分区：
文献类型：
--
作者：
Bundgaard, Jens R.;Rehfeld, Jens F.
前荷尔蒙通常在分泌之前经历广泛的细胞加工。这些翻译后加工事件发生在构成或调节分泌途径的细胞器中。这项研究的目的是研究翻译后修饰与孕激素多肽所采取的分泌途径的关系。孕激素是胃泌素的前体激素，在体内由幽门腺细胞分泌，刺激胃酸的释放。将孕激素定位于早期分泌途径的隔室表明，内蛋白降解过程是在内分泌细胞的前跨高尔基网络隔室启动的，而不是非内分泌细胞。由此产生的孕激素N端片段通过构成途径分泌，而内蛋白降解处理的C末端片段通过调节或类似构成途径分泌。来自孕激素的C-末端片段在羧酰胺化和酪氨酸硫化的水平和模式上具有不同的特征，与所采取的分泌途径相一致。引入分选基序的点突变破坏了这些模式，表明翻译后修饰的差异可归因于前体的不同细胞内分选。结果表明，孕激素的两步分选机制导致加工片段通过不同的分泌途径产生不同的分泌。
Prohormones often undergo extensive cellular processing prior to secretion. These post-translational processing events occur in organelles of the constitutive or regulated secretory pathway. The aim of this study was to examine the relationship between post-translational modifications and the secretory pathways taken by peptides derived from progastrin, the prohormone of gastrin, which in vivo is secreted by cells of the pyloric glands and stimulates the release of gastric acid. Targeting progastrin to compartments of the early secretory pathway shows that endoproteolytic processing is initiated in a pre-trans-Golgi network compartment of endocrine but not non-endocrine cells. The resulting N-terminal fragments of progastrin are secreted via the constitutive pathway, whereas endoproteolytically processed C-terminal fragments are secreted via the regulated or constitutive-like pathways. C-terminal fragments derived from progastrin differ in characteristic manners in levels and patterns of carboxyamidation and tyrosine sulfation in accordance with the secretory pathway taken. Point mutations introduced into a sorting motif disrupt these patterns, suggesting that differences in post-translational modifications are attributable to differential intracellular sorting of precursors. The results suggest a two-step sorting mechanism for progastrin leading to differential secretion of processed fragments via different secretory pathways.