title: The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress.
abstract: Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors (PERK, ATF6, and IRE1) implement the UPR. PERK phosphorylation of the α subunit of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins. Phosphorylation of eIF2α (eIF2α~P) also induces preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also for activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated and help explain the diverse biological defects associated with loss of PERK.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Teske
authors.forename: Sheree A
authors.initials: SA
authors.lastname: Wek
authors.forename: Piyawan
authors.initials: P
authors.lastname: Bunpo
authors.forename: Judy K
authors.initials: JK
authors.lastname: Cundiff
authors.forename: Jeanette N
authors.initials: JN
authors.lastname: McClintick
authors.forename: Tracy G
authors.initials: TG
authors.lastname: Anthony
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D014158:Transcription, Genetic; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D051701:Activating Transcription Factor 4; D051702:Activating Transcription Factor 6; D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C497112:Atf6 protein, mouse; C486556:Ern2 protein, mouse; C531557:eIF2alpha kinase, mouse