Sec61 and ER Stress in Beta-cell Function and Type 2 Diabetes

摘要 在表型驱动的遗传筛选中，识别影响细胞的新基因 功能，我们在一个糖尿病小鼠家族中发现了Sec61a1的突变。 Sec61a1编码内质网的蛋白质传导亚单位 (Er)转位通道，负责将蛋白质输入内质网。 Sec61a1突变小鼠的糖尿病与细胞凋亡和 大量扩张的急诊室。扩张的内质网与内质网应激一致， 未折叠的蛋白质在内质网内的积累。细胞对此作出反应 内质网应激，未折叠的蛋白质反应，包括蛋白质上调 折叠伴侣(例如Bip)，以及在不能缓解内质网应激的情况下， 促凋亡转录因子CHOP的上调。Bip和Chop是 这两种基因在糖尿病Sec61a1突变动物中表达上调。因此，我们的假设是 Sec61a1突变导致内质网应激、细胞凋亡和糖尿病。这个 这一方案中的实验旨在检验这一假设，以了解 Sec61a1突变导致内质网应激的机制 压力在作为2型糖尿病一部分的细胞功能障碍中起着作用。

Abstract In a phenotype-driven, genetic screen to identify novel genes that affect ¿-cell function, we found a mutation in Sec61a1 in a family of mice with diabetes. Sec61a1 encodes the protein conducting subunit of the endoplasmic reticulum (ER) translocation channel, which is responsible for protein import into the ER. Diabetes in Sec61a1 mutant mice is correlated with ¿-cell apoptosis and massively distended ER. The distended ER is consistent with ER stress, an accumulation of unfolded proteins within the ER. The cell mounts a response to ER stress, the unfolded protein response, which includes up regulation of protein folding chaperones (e.g. Bip), and, in the case that ER stress cannot be relieved, up regulation of the proapoptotic transcription factor Chop. Bip and Chop are both up regulated in diabetic Sec61a1 mutant animals. Thus, our hypothesis is that Sec61a1 mutation leads to ER stress, ¿-cell apoptosis, and diabetes. The experiments in this proposal are designed to test this hypothesis, to understand the mechanism by which Sec61a1 mutation leads to ER stress, and to ask if ER stress plays a role in the ¿-cell dysfunction that is part of type 2 diabetes.