PERK (EIF2AK3) Regulates Proinsulin Trafficking and Quality Control in the Secretory Pathway

被引:116
作者
Gupta, Sounak [1 ]
McGrath, Barbara [1 ]
Cavener, Douglas R. [1 ]
机构
[1] Penn State Univ, Dept Biol, Huck Inst Life Sci, Penn State Inst Diabet & Obes, University Pk, PA 16802 USA
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; UNFOLDED-PROTEIN RESPONSE; PANCREATIC BETA-CELLS; TO-GOLGI TRANSPORT; EIF2-ALPHA KINASE; INSULIN-SECRETION; DIABETES-MELLITUS; ER STRESS; ACTIVATION; PROLIFERATION;
D O I
10.2337/db09-1064
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE-Loss-of-function mutations in Perk (EIF2AK3) result in permanent neonatal diabetes in humans (Wolcott-Raison 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. RESEARCH DESIGN AND METHODS-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. RESULTS-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 CONCLUSIONS-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. Diabetes 59:1937-1947, 2010
引用
收藏
页码:1937 / 1947
页数:11
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