title: Translational control is required for the unfolded protein response and in vivo glucose homeostasis.
abstract: The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2alpha phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2alpha 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 beta cells. The results demonstrate that regulation of translation through eIF2alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.
authors: Howard Hughes Medical Institute, University of Michigan Medical Center, 48109, Ann Arbor, MI, USA.
authors: D
authors: D
authors: Scheuner
authors: B
authors: B
authors: Song
authors: E
authors: E
authors: McEwen
authors: C
authors: C
authors: Liu
authors: R
authors: R
authors: Laybutt
authors: P
authors: P
authors: Gillespie
authors: T
authors: T
authors: Saunders
authors: S
authors: S
authors: Bonner-Weir
authors: R J
authors: RJ
authors: Kaufman
mesh_terms: D051696:Activating Transcription Factors; D000818:Animals; D000831:Animals, Newborn; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression / Q000502:physiology; D018095:Germ-Line Mutation; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006706:Homeostasis / Q000502:physiology*; D006720:Homozygote; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis / Q000502:physiology; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D017510:Protein Folding; D012333:RNA, Messenger / Q000032:analysis; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D051696:Activating Transcription Factors; D001798:Blood Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D005947:Glucose