[PDF][PDF] Translational control is required for the unfolded protein response and in vivo glucose homeostasis

D Scheuner, B Song, E McEwen, C Liu, R Laybutt… - Molecular cell, 2001 - cell.com
D Scheuner, B Song, E McEwen, C Liu, R Laybutt, P Gillespie, T Saunders, S Bonner-Weir
Molecular cell, 2001cell.com
The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein
synthesis initiation through phosphorylation of the α subunit of eukaryotic translation
initiation factor 2 (eIF2α) at Ser51. Subsequently, transcription of genes encoding adaptive
functions including the glucose-regulated proteins is induced. We show that eIF2α
phosphorylation is required for translation attenuation, transcriptional induction, and survival
in response to ER stress. Mice with a homozygous mutation at the eIF2α phosphorylation …
Abstract
The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2α phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic β cells. The results demonstrate that regulation of translation through eIF2α phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.
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