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

The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the cu subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2 alpha. phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2 alpha 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 P cells. The results demonstrate that regulation of translation through eIF2 alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.