Endoplasmic Reticulum-Associated Degradation (ERAD) Has a Critical Role in Supporting Glucose-Stimulated Insulin Secretion in Pancreatic -Cells
Endoplasmic Reticulum-Associated Degradation (ERAD) Has a Critical Role in Supporting Glucose-Stimulated Insulin Secretion in Pancreatic -Cells
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内质网相关降解 (ERAD) 在支持胰腺 β 细胞中葡萄糖刺激的胰岛素分泌中发挥着关键作用。
DOI：
10.2337/db18-0624
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发表时间：
2019-04-01
期刊：
影响因子：
7.7
通讯作者：
Long, Qiaoming
中科院分区：
文献类型：
--
作者：
Hu, Yabing;Gao, Yuanyuan;Long, Qiaoming
导致糖尿病的细胞功能障碍和死亡的分子基础尚未完全阐明。本研究的目的是探讨内质网相关降解（ERAD）在胰腺细胞中的作用。化学诱导的大鼠胰岛素瘤细胞系INS-1 ERAD缺乏显著降低葡萄糖刺激胰岛素分泌（GSIS）。研究人员在ERAD核心蛋白SEL1L基因消融导致ERAD缺失的细胞和小鼠中研究了这种效应的机制基础。在INS-1细胞和小鼠胰腺细胞中靶向破坏SEL1L会损害ERAD并导致GSIS钝化。此外，细胞中SEL1L缺失的小鼠在出生后出现慢性高血糖，随着时间的推移，葡萄糖耐受性越来越差。在INS-1细胞和小鼠胰腺细胞中，SEL1L缺失导致胰岛素原在内质网腔室中被包裹。折叠能力和折叠缺陷胰岛素原均可与ERAD复合体的E3泛素连接酶亚基HRD1发生生理相互作用并被其有效降解。胰岛素瘤细胞的GSIS损伤伴随着细胞内Ca2+离子水平的降低、活性氧的过量产生和线粒体膜电位的降低。总之，这些发现表明ERAD通过靶向野生型和折叠缺陷的胰岛素原蛋白体降解，在支持胰腺细胞功能方面起着关键作用。ERAD缺乏可能通过影响内质网中的胰岛素原加工、细胞内Ca2+浓度和线粒体功能而促进糖尿病的发展。
The molecular underpinnings of -cell dysfunction and death leading to diabetes are not fully elucidated. The objective of the current study was to investigate the role of endoplasmic reticulum-associated degradation (ERAD) in pancreatic -cells. Chemically induced ERAD deficiency in the rat insulinoma cell line INS-1 markedly reduced glucose-stimulated insulin secretion (GSIS). The mechanistic basis for this effect was studied in cells and mice lacking ERAD as a consequence of genetic ablation of the core ERAD protein SEL1L. Targeted disruption of SEL1L in INS-1 cells and in mouse pancreatic -cells impaired ERAD and led to blunted GSIS. Additionally, mice with SEL1L deletion in -cells were chronically hyperglycemic after birth and increasingly glucose intolerant over time. SEL1L absence caused an entrapment of proinsulin in the endoplasmic reticulum compartment in both INS-1 cells and mouse pancreatic -cells. Both folding-competent and folding-deficient proinsulin can physiologically interact with and be efficiently degraded by HRD1, the E3 ubiquitin ligase subunit of the ERAD complex. GSIS impairment in insulinoma cells was accompanied by a reduced intracellular Ca2+ ion level, overproduction of reactive oxygen species, and lowered mitochondrial membrane potential. Together, these findings suggest that ERAD plays a pivotal role in supporting pancreatic -cell function by targeting wild-type and folding-deficient proinsulin for proteosomal degradation. ERAD deficiency may contribute to the development of diabetes by affecting proinsulin processing in the ER, intracellular Ca2+ concentration, and mitochondrial function.