Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload.
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.
Oyadomari
Seiichi
S
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Yun
Chi
C
Fisher
Edward A
EA
Kreglinger
Nicola
N
Kreibich
Gert
G
Oyadomari
Miho
M
Harding
Heather P
HP
Goodman
Alan G
AG
Harant
Hanna
H
Garrison
Jennifer L
JL
Taunton
Jack
J
Katze
Michael G
MG
Ron
David
D
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
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