title: Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK.
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.
authors.affiliation: Departments of Microbiology and Laboratory Medicine, School of Medicine, and Washington National Primate Research Center, University of Washington, Seattle, WA 98195, USA. wyan96@u.washington.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Frank
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Isabel
authors.initials: I
authors.lastname: Novoa
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006031:Glycosylation / Q000187:drug effects; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000502:physiology*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013234:Stem Cells / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004229:Dithiothreitol; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D014415:Tunicamycin; D019892:eIF-2 Kinase; C494651:DNAJC3 protein, human; C497250:Ddit3 protein, mouse; C500846:Dnajc3 protein, mouse