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 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.
Scheuner
D
D
Howard Hughes Medical Institute, University of Michigan Medical Center, 48109, Ann Arbor, MI, USA.
Song
B
B
McEwen
E
E
Liu
C
C
Laybutt
R
R
Gillespie
P
P
Saunders
T
T
Bonner-Weir
S
S
Kaufman
R J
RJ
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
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