D. Scheuner et al., Translational control is required for the unfolded protein response and invivo glucose homeostasis, MOL CELL, 7(6), 2001, pp. 1165-1176
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.