Cunningham Corey N, He Kaiyu, Arunagiri Anoop, Paton Adrienne W, Paton James C, Arvan Peter, Tsai Billy
Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI.
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI.
Diabetes. 2017 Mar;66(3):741-753. doi: 10.2337/db16-1338. Epub 2016 Dec 27.
In heterozygous patients with a diabetic syndrome called mutant gene-induced diabetes of youth (MIDY), there is decreased insulin secretion when mutant proinsulin expression prevents wild-type (WT) proinsulin from exiting the endoplasmic reticulum (ER), which is essential for insulin production. Our previous results revealed that mutant proinsulin is triaged by ER-associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shifting proinsulin from high-molecular weight (MW) complexes toward smaller oligomeric species that are competent to undergo ERAD. Strikingly, overexpressing Grp170 also liberates WT proinsulin, which is no longer trapped in these high-MW complexes, enhancing ERAD of proinsulin and restoring WT insulin secretion. Our data reveal that Grp170 participates in preparing mutant proinsulin for degradation while enabling WT proinsulin escape from the ER. In principle, selective destruction of mutant proinsulin offers a rational approach to rectify the insulin secretion problem in MIDY.
在患有一种名为突变基因诱导的青年糖尿病（MIDY）的糖尿病综合征的杂合患者中，当突变胰岛素原的表达阻止野生型（WT）胰岛素原离开内质网（ER）时，胰岛素分泌会减少，而内质网对于胰岛素的产生至关重要。我们之前的结果表明，突变胰岛素原通过内质网相关降解（ERAD）进行分选。我们现在发现，内质网伴侣蛋白Grp170通过将胰岛素原从高分子量（MW）复合物转变为能够进行ERAD的较小寡聚体物种来参与降解过程。令人惊讶的是，过表达Grp170还能释放WT胰岛素原，使其不再被困在这些高分子量复合物中，增强胰岛素原的ERAD并恢复WT胰岛素分泌。我们的数据表明，Grp170参与为突变胰岛素原的降解做准备，同时使WT胰岛素原能够从内质网中逃逸。原则上，选择性破坏突变胰岛素原为纠正MIDY中的胰岛素分泌问题提供了一种合理的方法。
