A decrease in cellular energy status stimulates PERK-dependent eIF2 alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells

In the present study, we demonstrate that, in pancreatic cells, eIF2 alpha (eukaryotic initiation factor 2 alpha) phosphorylation in response to a decrease in glucose concentration is primarily mediated by the activation of PERK [PKR (protein kinase RNA activated)-like endoplasmic reticulum kinase]. We provide evidence that this increase in PERK activity is evoked by a decrease in the energy status of the cell via a potentially novel mechanism that is independent of IRE1 (inositol requiring enzyme 1) activation and the accumulation of unfolded nascent proteins within the endoplasmic reticulum. The inhibition of eIF2a phosphorylation in glucose-deprived cells by the overexpression of dominant-negative PERK or an N-terminal truncation mutant of GADD34 (growth-arrest and DNA-damage-inducible protein 34) leads to a 53 % increase in the rate of total protein synthesis. Polysome analysis revealed that this coincides with an increase in the amplitude but not the number of ribosomes per mRNA, indicating that eIF2 alpha dephosphorylation mobilizes hitherto untranslated mRNAs on to polysomes. In summary, we show that PERK is activated at low glucose concentrations in response to a decrease in energy status and that this plays an important role in glucose-regulated protein synthesis in pancreatic beta-cells.

作 者：

Gomez, E；Powell, ML；Bevington, A；Herbert, TP

刊 名：

The Biochemical Journal 

年，卷(期)：

2008vol.410(no.3) 

分类号：

 

关键词：

beta-cell  energy status  eukaryotic initiation factor 2 alpha (eIF2 alpha)  glucose  protein kinase RNA-activated (PKR)-like endoplasmic reticulum kinase (PERK)  translation  ENDOPLASMIC-RETICULUM STRESS  TRANSLATIONAL CONTROL  PROINSULIN BIOSYNTHESIS  ER STRESS  GLUCOSE-HOMEOSTASIS  INITIATION  KINASE  INSULIN  INHIBITION  ISLETS

正文语种：

eng 

基金项目：