Translation Attenuation through elF2α Phosphorylation Prevents Oxidative Stress and Maintains the Differentiated State in β Cells

Accumulation of unfolded protein within the endoplasmic reticulum (ER) attenuates mRNA translation through PERK-mediated phosphorylation of eukaryotic initiation factor 2 on Ser51 of the alpha subunit (elF2 alpha). To elucidate the role of elF2 alpha phosphorylation, we engineered mice for conditional expression of homozygous Ser51 Ala mutant elF2 alpha. The absence of elF2 alpha phosphorylation in 0 cells caused a severe diabetic phenotype due to heightened and unregulated proinsulin translation; defective intracellular trafficking of ER cargo proteins; increased oxidative damage; reduced expression of stress response and beta-cell-specific genes; and apoptosis. However, glucose intolerance and beta cell death in these mice were attenuated by a diet containing antioxidant. We conclude that phosphorylation of elF2 alpha coordinately attenuates mRNA translation, prevents oxidative stress, and optimizes ER protein folding to suppo insulin production. The finding that increased proinsulin synthesis causes oxidative damage in beta cells may reflect events in the beta cell failure associated with insulin resistance in type 2 diabetes.