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A decrease in cellular energy status stimulates PERK-dependent eIF2α phosphorylation and regulates protein synthesis in pancreatic β-cells

By Edith Gomez, Mike L. Powell, Alan Bevington and Terence P. Herbert

Abstract

This is the author’s final draft of the paper published as Biochemical Journal, 2008, 410 (3), pp. 485-493. The final published version is available at http://www.biochemj.org/bj/410/bj4100485.htm, Doi: 10.1042/BJ20071367.In the present study, we demonstrate that, in pancreatic β-cells, eIF2α (eukaryotic initiation factor 2α) 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 eIF2α 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 eIF2α 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 β-cells.This work was supported by a Wellcome Trust Project Grant (awarded to TPH). EG was supported by the Wellcome Trust. MLP was supported by an MRC studentship. We would also like to thank Professors Ron Wek, David Ron and Chris Proud for generously providing reagents

Topics: β-cell, energy status, eukaryotic initiation factor 2α (eIF2α), glucose, protein kinase RNA-activated (PKR)-like endoplasmic reticulum kinase (PERK), translation
Publisher: Portland Press
Year: 2007
DOI identifier: 10.1042/BJ20071367
OAI identifier: oai:lra.le.ac.uk:2381/8062
Journal:

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Citations

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