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

The accumulation of unfolded protein in the endoplasmic reticulum (ER) atte nuates protein synthesis initiation through phosphorylation of the cu subun it of eukaryotic translation initiation factor 2 (eIF2 alpha) at Ser51. Sub sequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2 alpha. phosphoryl ation is required for translation attenuation, transcriptional induction, a nd survival in response to ER stress. Mice with a homozygous mutation at th e 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 pancreati c P cells. The results demonstrate that regulation of translation through e IF2 alpha phosphorylation is essential for the ER stress response and in vi vo glucose homeostasis.