PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway.
PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway.
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DOI：
10.2337/db09-1064
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发表时间：
2010-08
期刊：
影响因子：
7.7
通讯作者：
Cavener DR
中科院分区：
文献类型：
--
作者：
Gupta S;McGrath B;Cavener DR
Perk （EIF2AK3）的功能缺失突变导致人类（Wolcott-Rallison综合征）和小鼠的永久性新生儿糖尿病。先前，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β细胞表现出高度异常的细胞表型，其特征是内质网（ER）严重扩张和胰岛素原保留。我们研究了过度合成、缺乏内质网相关降解（ERAD）和内质网缺陷导致高尔基体转运的可能原因。在细胞培养和PERK受损或基因剂量调节的小鼠中研究了PERK的内质网功能。以Ins2+/秋田突变小鼠为模型系统，检测PERK在ERAD中的作用。我们报道Perk功能的丧失不会导致不受控制的蛋白质合成，但会损害内质网到高尔基体的顺行运输，从内质网到细胞质的逆行易位以及蛋白酶体降解。PERK也被证明是维持内质网和高尔基体的完整性以及ATF6处理所必需的。此外，减少Perk的剂量令人惊讶地改善了秋田突变体向糖尿病的进展。PERK是ERAD和蛋白酶体活性的正向调节因子。降低PERK活性可改善秋田小鼠糖尿病的进展，而增加PERK剂量可加速其进展。我们推测PERK在胰岛素分泌β细胞中作为代谢传感器，调节内质网中胰岛素原的运输和质量控制，以满足循环胰岛素的生理需求。
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 β-cells and from defects in insulin secretion. A substantial fraction of PERK-deficient β-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 β-cells to modulate the trafficking and quality control of proinsulin in the ER relative to the physiological demands for circulating insulin.