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

Mol Cell. 2001 Jun;7(6):1165-76. doi: 10.1016/s1097-2765(01)00265-9.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factors
  • Animals
  • Animals, Newborn
  • Blood Proteins / genetics
  • Blood Proteins / metabolism
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Survival / physiology
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / metabolism
  • Gene Expression / physiology
  • Germ-Line Mutation
  • Gluconeogenesis / physiology
  • Glucose / metabolism*
  • Heat-Shock Proteins*
  • Homeostasis / physiology*
  • Homozygote
  • Hypoglycemia / genetics
  • Hypoglycemia / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Mutant Strains
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Mutagenesis / physiology
  • Phosphorylation
  • Protein Biosynthesis / physiology*
  • Protein Folding
  • RNA, Messenger / analysis
  • Transcription Factor CHOP
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation / physiology

Substances

  • Activating Transcription Factors
  • Blood Proteins
  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • DNA-Binding Proteins
  • Ddit3 protein, mouse
  • Heat-Shock Proteins
  • Molecular Chaperones
  • RNA, Messenger
  • Transcription Factors
  • Transcription Factor CHOP
  • Glucose
  • molecular chaperone GRP78