eLife：胰岛素囊泡成熟过程调控新机制

10月18日，eLife 杂志在线发表了中国科学院生物物理研究所徐涛课题组题为HID-1 is required for homotypic fusion of immature secretory granules during maturation 的文章，报道Hid-1蛋白参与胰岛素囊泡成熟的调控过程。

细胞内的肽类激素或者神经肽类物质都被储存于一类特定的细胞器中，它们被称为致密核心囊泡（DCV）。致密核心囊泡在高尔基区出芽形成未成熟囊泡，在运输途中需要经过同型融合、货物分选等一系列复杂的过程才能够形成成熟的可分泌的囊泡。目前人们对这一生物学过程知之甚少。

徐涛课题组之前的研究表明，主要定位于高尔基体的HID-1蛋白在胰岛β细胞等分泌细胞中高表达，并在囊泡的运输和成熟过程中起作用。为了进一步研究该蛋白的生理功能，研究人员构建了胰岛β细胞特异性敲除Hid-1基因的小鼠模型。HID-1敲除小鼠表现出明显的糖耐量异常，其胰岛素分泌不足并且胰岛素原的剪切存在严重缺陷。同时，电镜分析发现，该小鼠胰岛β细胞中致密核心囊泡的致密程度不足，直径偏小。进一步的体外实验证明， HID-1蛋白是胰岛素囊泡的同型融合过程的重要参与者，HID-1蛋白的缺乏直接造成同型融合受阻，并且抑制胰岛素囊泡酸化的过程。该研究表明 HID-1是一个全新的、能够直接影响胰岛素囊泡成熟的蛋白，首次在动物模型上证明了同型融合对于胰岛β细胞释放胰岛素有重要意义。

研究员徐涛、徐平勇以及高级工程师薛艳红是该文的通讯作者，徐涛课题组的杜雯、周茂阁、赵炜、程冬婉为共同第一作者，该研究得到国家重点研发计划、国家自然科学基金等项目的资助。

图示：Hid-1缺失影响胰岛素囊泡同型融合的过程。　

原文摘要：

HID-1 is required for homotypic fusion of immature secretory granules during maturation

Secretory granules, also known as dense core vesicles, are generated at the trans-Golgi network and undergo several maturation steps, including homotypic fusion of immature secretory granules (ISGs), and processing of prehormones to yield active peptides. The molecular mechanisms governing secretory granule maturation are largely unknown. Here, we investigate a highly conserved protein named HID-1 in a mouse model. A conditional knockout of HID-1 in pancreatic β cells leads to glucose intolerance and a remarkable increase in the serum proinsulin/insulin ratio caused by defective proinsulin processing. Large volume three-dimensional electron microscopy and immunofluorescence imaging reveal that ISGs are much more abundant in the absence of HID-1. We further demonstrate that HID-1 deficiency prevented secretory granule maturation by blocking homotypic fusion of immature secretory granules. Our data identify a novel player during the early maturation of immature secretory granules.