Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK

Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15920-5. doi: 10.1073/pnas.252341799. Epub 2002 Nov 22.

Abstract

P58(IPK) is an Hsp40 family member known to inhibit the interferon (IFN)-induced, double-stranded RNA-activated, eukaryotic initiation factor 2alpha (eIF2alpha) protein kinase R (PKR) by binding to its kinase domain. We find that the stress of unfolded proteins in the endoplasmic reticulum (ER) activates P58(IPK) gene transcription through an ER stress-response element in its promoter region. P58(IPK) interacts with and inhibits the PKR-like ER-localized eIF2alpha kinase PERK, which is normally activated during the ER-stress response to protect cells from ER stress by attenuating protein synthesis and reducing ER client protein load. Levels of phosphorylated eIF2alpha were lower in ER-stressed P58(IPK)-overexpressing cells and were enhanced in P58(IPK) mutant cells. In the ER-stress response, PKR-like ER kinase (PERK)-mediated translational repression is transient and is followed by translational recovery and enhanced expression of genes that increase the capacity of the ER to process client proteins. The absence of P58(IPK) resulted in increased expression levels of two ER stress-inducible genes, BiP and Chop, consistent with the enhanced eIF2alpha phosphorylation in the P58(IPK) deletion cells. Our studies suggest that P58(IPK) induction during the ER-stress response represses PERK activity and plays a functional role in the expression of downstream markers of PERK activity in the later phase of the ER-stress response.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins / biosynthesis
  • CCAAT-Enhancer-Binding Proteins / genetics
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Dithiothreitol / pharmacology
  • Endoplasmic Reticulum / metabolism*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression Regulation
  • Gene Targeting
  • Glycosylation / drug effects
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones / biosynthesis
  • Molecular Chaperones / genetics
  • Molecular Sequence Data
  • Oxidation-Reduction
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic
  • Protein Folding
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / physiology*
  • Recombinant Fusion Proteins / physiology
  • Regulatory Sequences, Nucleic Acid*
  • Repressor Proteins / physiology*
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Stem Cells / metabolism
  • Stress, Physiological / metabolism
  • Thapsigargin / pharmacology
  • Transcription Factor CHOP
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription, Genetic
  • Tunicamycin / pharmacology
  • eIF-2 Kinase / physiology*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • DNAJC3 protein, human
  • Ddit3 protein, mouse
  • Dnajc3 protein, mouse
  • Eukaryotic Initiation Factor-2
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Transcription Factors
  • Tunicamycin
  • Transcription Factor CHOP
  • Thapsigargin
  • PERK kinase
  • eIF-2 Kinase
  • Dithiothreitol
  • molecular chaperone GRP78

Associated data

  • GENBANK/AF495532