Department of Biology, The Huck Institutes of the Life Sciences, Penn State Institute for Diabetes and Obesity, Pennsylvania State University, University Park, Pennsylvania, USA.
Diabetes. 2010 Aug;59(8):1937-47. doi: 10.2337/db09-1064. Epub 2010 Jun 8.
Loss-of-function mutations in Perk (EIF2AK3) result in permanent neonatal diabetes in humans (Wolcott-Rallison Syndrome) and mice. Previously, we found that diabetes associated with Perk deficiency resulted from insufficient proliferation of beta-cells and from defects in insulin secretion. A substantial fraction of PERK-deficient beta-cells display a highly abnormal cellular phenotype characterized by grossly distended endoplasmic reticulum (ER) and retention of proinsulin. We investigated over synthesis, lack of ER-associated degradation (ERAD), and defects in ER to Golgi trafficking as possible causes.
ER functions of PERK were investigated in cell culture and mice in which Perk was impaired or gene dosage modulated. The Ins2(+/Akita) mutant mice were used as a model system to test the role of PERK in ERAD.
We report that loss of Perk function does not lead to uncontrolled protein synthesis but impaired ER-to-Golgi anterograde trafficking, retrotranslocation from the ER to the cytoplasm, and proteasomal degradation. PERK was also shown to be required to maintain the integrity of the ER and Golgi and processing of ATF6. Moreover, decreasing Perk dosage surprisingly ameliorates the progression of the Akita mutants toward diabetes.
PERK is a positive regulator of ERAD and proteasomal activity. Reducing PERK activity ameliorates the progression of diabetes in the Akita mouse, whereas increasing PERK dosage hastens its progression. We speculate that PERK acts as a metabolic sensor in the insulin-secreting beta-cells to modulate the trafficking and quality control of proinsulin in the ER relative to the physiological demands for circulating insulin.
Perk（EIF2AK3）的功能丧失突变导致人类（Wolcott-Rallison 综合征）和小鼠的永久性新生儿糖尿病。以前，我们发现与 Perk 缺乏相关的糖尿病是由于β细胞增殖不足和胰岛素分泌缺陷引起的。相当一部分 PERK 缺陷的β细胞表现出高度异常的细胞表型，其特征为内质网（ER）严重扩张和胰岛素原滞留。我们研究了过度合成、缺乏 ER 相关降解（ERAD）以及 ER 到高尔基体运输缺陷作为可能的原因。
在细胞培养和 Perk 受损或基因剂量调节的小鼠中研究了 PERK 的 ER 功能。Ins2(+/Akita) 突变小鼠被用作测试 PERK 在 ERAD 中的作用的模型系统。
我们报告说，Perk 功能的丧失不会导致不受控制的蛋白质合成，而是会导致 ER 到高尔基体顺行运输、从 ER 逆行到细胞质以及蛋白酶体降解受损。还表明 PERK 对于维持 ER 和高尔基体的完整性以及 ATF6 的加工是必需的。此外，降低 Perk 剂量出人意料地改善了 Akita 突变体向糖尿病的进展。
PERK 是 ERAD 和蛋白酶体活性的正调节剂。降低 PERK 活性可改善 Akita 小鼠糖尿病的进展，而增加 PERK 剂量则会加速其进展。我们推测 PERK 在胰岛素分泌β细胞中作为代谢传感器起作用，以相对于循环胰岛素的生理需求调节 ER 中胰岛素原的运输和质量控制。
