TY - JOUR
T1 - Cotranslocational Degradation Protects the Stressed Endoplasmic Reticulum from Protein Overload
AU - Oyadomari, Seiichi
AU - Yun, Chi
AU - Fisher, Edward A.
AU - Kreglinger, Nicola
AU - Kreibich, Gert
AU - Oyadomari, Miho
AU - Harding, Heather P.
AU - Goodman, Alan G.
AU - Harant, Hanna
AU - Garrison, Jennifer L.
AU - Taunton, Jack
AU - Katze, Michael G.
AU - Ron, David
N1 - Funding Information:
We thank Jennifer Hui, Kazutaka Araki, Rivka Jungreis, and Cristina Villagra (NYU) for their assistance with various phases of this project; Berndt Oberhauser and Shirley Wang (Novartis) for synthesis of CAM741 and construction of the VCAM1 plasmids; Ron Kopito (Stanford University) for the HA-tagged TCRa clone; Virginia Black (NYU) for the antiserum to CYP1A1; Peter Walter (UCSF) for the anti-puromycin antibody; and Ramanujan Hegde (NIH) and Cole Haynes (NYU) for advice. Supported by NIH grants DK47119 and ES08681 to D.R., HL58541 to E.A.F., and fellowships from JDRF and the Uehara Memorial Foundation to S.O. H.H. is employed by Novartis and owns stock options and restricted stock units. The authors have no other conflicting financial interests.
PY - 2006/8/25
Y1 - 2006/8/25
N2 - 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 P58IPK/DNAJC3, a UPR-responsive gene previously implicated in translational control, encodes a cytosolic cochaperone that associates with the ER protein translocation channel Sec61. P58IPK 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 P58IPK-/- mice, cells with a high secretory burden are markedly compromised in their ability to cope with ER stress. Thus, P58IPK is a key mediator of cotranslocational ER protein degradation, and this process likely contributes to ER homeostasis in stressed cells.
AB - 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 P58IPK/DNAJC3, a UPR-responsive gene previously implicated in translational control, encodes a cytosolic cochaperone that associates with the ER protein translocation channel Sec61. P58IPK 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 P58IPK-/- mice, cells with a high secretory burden are markedly compromised in their ability to cope with ER stress. Thus, P58IPK is a key mediator of cotranslocational ER protein degradation, and this process likely contributes to ER homeostasis in stressed cells.
UR - https://www.scopus.com/pages/publications/33747175431
U2 - 10.1016/j.cell.2006.06.051
DO - 10.1016/j.cell.2006.06.051
M3 - Article
C2 - 16923392
AN - SCOPUS:33747175431
SN - 0092-8674
VL - 126
SP - 727
EP - 739
JO - Cell
JF - Cell
IS - 4
ER -