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Human Molecular Genetics Advance Access originally published online on August 15, 2005
Human Molecular Genetics 2005 14(19):2787-2799; doi:10.1093/hmg/ddi312
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Endoplasmic reticulum stress compromises the ubiquitin–proteasome system

Victoria Menéndez-Benito1, Lisette G.G.C. Verhoef1, Maria G. Masucci2 and Nico P. Dantuma1,*

1Department of Cell and Molecular Biology, The Medical Nobel Institute, Karolinska Institutet, PO Box 285, Von Eulers väg 3, S-171 77 Stockholm, Sweden and 2Microbiology and Tumor Biology Center, Karolinska Institutet, Nobels väg 16, S-171 77 Stockholm, Sweden

* To whom correspondence should be addressed. Tel: +46 852487384; Fax: +46 8313529; Email: nico.dantuma{at}cmb.ki.se

Received May 2, 2005; Revised July 21, 2005; Accepted August 9, 2005

The presence of endoplasmic reticulum (ER) stress and impaired ubiquitin–proteasome system (UPS) activity has been independently implicated in the pathophysiology of conformational diseases. Here, we reveal a link between ER stress and the functionality of the UPS. Treatment of cells with different ER stressors delayed the degradation of an ER reporter substrate and caused a subtle but consistent accumulation of three independent nuclear/cytosolic UPS reporter substrates. A similar signature increase was observed upon induction of ER stress in transgenic mice expressing a reporter substrate. Cells undergoing ER stress failed to clear efficiently UBB+1, an aberrant ubiquitin found in conformational diseases, which in turn caused general impairment of the UPS. We conclude that ER stress has a general inhibitory effect on the UPS. The compromised UPS during ER stress may explain the long-term gradual accumulation of misfolded proteins as well as the selective vulnerability of particular cell populations in conformational diseases.


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