title: Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload.
abstract: The ER's capacity to process proteins is limited, and stress caused by accumulation of unfolded and misfolded proteins (ER stress) contributes to human disease. ER stress elicits the unfolded protein response (UPR), whose components attenuate protein synthesis, increase folding capacity, and enhance misfolded protein degradation. Here, we report that P58(IPK)/DNAJC3, a UPR-responsive gene previously implicated in translational control, encodes a cytosolic cochaperone that associates with the ER protein translocation channel Sec61. P58(IPK) recruits HSP70 chaperones to the cytosolic face of Sec61 and can be crosslinked to proteins entering the ER that are delayed at the translocon. Proteasome-mediated cytosolic degradation of translocating proteins delayed at Sec61 is cochaperone dependent. In P58(IPK-/-) mice, cells with a high secretory burden are markedly compromised in their ability to cope with ER stress. Thus, P58(IPK) is a key mediator of cotranslocational ER protein degradation, and this process likely contributes to ER homeostasis in stressed cells.
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: Chi
authors.initials: C
authors.lastname: Yun
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Nicola
authors.initials: N
authors.lastname: Kreglinger
authors.forename: Gert
authors.initials: G
authors.lastname: Kreibich
authors.forename: Miho
authors.initials: M
authors.lastname: Oyadomari
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: Alan G
authors.initials: AG
authors.lastname: Goodman
authors.forename: Hanna
authors.initials: H
authors.lastname: Harant
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Garrison
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: David
authors.initials: D
authors.lastname: Ron
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000502:physiology*; D000069816:SEC Translocation Channels; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D007328:Insulin; D008565:Membrane Proteins; D018832:Molecular Chaperones; D000069816:SEC Translocation Channels; D019010:Vascular Cell Adhesion Molecule-1; D019892:eIF-2 Kinase; C500846:Dnajc3 protein, mouse