title: Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2.
abstract: Transient phosphorylation of the alpha-subunit of translation initiation factor 2 (eIF2alpha) represses translation and activates select gene expression under diverse stressful conditions. Defects in the eIF2alpha phosphorylation-dependent integrated stress response impair resistance to accumulation of malfolded proteins in the endoplasmic reticulum (ER stress), to oxidative stress and to nutrient deprivations. To study the hypothesized protective role of eIF2alpha phosphorylation in isolation of parallel stress signaling pathways, we fused the kinase domain of pancreatic endoplasmic reticulum kinase (PERK), an ER stress-inducible eIF2alpha kinase that is normally activated by dimerization, to a protein module that binds a small dimerizer molecule. The activity of this artificial eIF2alpha kinase, Fv2E-PERK, is subordinate to the dimerizer and is uncoupled from upstream stress signaling. Fv2E-PERK activation enhanced the expression of numerous stress-induced genes and protected cells from the lethal effects of oxidants, peroxynitrite donors and ER stress. Our findings indicate that eIF2alpha phosphorylation can initiate signaling in a cytoprotective gene expression pathway independently of other parallel stress-induced signals and that activation of this pathway can single-handedly promote a stress-resistant preconditioned state.
authors.affiliation: Skirball Institute, New York University School of Medicine, New York, NY, USA.
authors.forename: Phoebe D
authors.initials: PD
authors.lastname: Lu
authors.forename: Céline
authors.initials: C
authors.lastname: Jousse
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Isabel
authors.initials: I
authors.lastname: Novoa
authors.forename: Donalyn
authors.initials: D
authors.lastname: Scheuner
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
mesh_terms: D051701:Activating Transcription Factor 4; D000818:Animals; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D019610:Cytoprotection; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D005971:Glutamates / Q000633:toxicity; D051379:Mice; D018384:Oxidative Stress; D010179:Pancreas / Q000201:enzymology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: C463061:AP20187; C081452:Atf4 protein, mouse; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D005971:Glutamates; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D019284:Thapsigargin; D019892:eIF-2 Kinase; D016559:Tacrolimus