Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta 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 (eIF2alpha). To elucidate the role of eIF2alpha phosphorylation, we engineered mice for conditional expression of homozygous Ser51Ala mutant eIF2alpha. The absence of eIF2alpha phosphorylation in beta 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 eIF2alpha coordinately attenuates mRNA translation, prevents oxidative stress, and optimizes ER protein folding to support 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.
Back
Sung Hoon
SH
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-0650, USA.
Scheuner
Donalyn
D
Han
Jaeseok
J
Song
Benbo
B
Ribick
Mark
M
Wang
Junying
J
Gildersleeve
Robert D
RD
Pennathur
Subramaniam
S
Kaufman
Randal J
RJ
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006720:Homozygote; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017510:Protein Folding; D021381:Protein Transport; D015398:Signal Transduction
D015852:Eukaryotic Initiation Factor-2; D007328:Insulin; D050505:Mutant Proteins