Human Molecular Genetics Advance Access published online on August 15, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi312
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1 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Von Eulers väg 3, S-171 77 Stockholm, Sweden
* To whom correspondence should be addressed. 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.
Article
Endoplasmic Reticulum Stress Compromises The Ubiquitin-Proteasome System
2 Microbiology and Tumor Biology Center, Karolinska Institutet, Nobels väg 16, S-171 77 Stockholm, Sweden
3 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Box 285, Von Eulers väg 3, S-171 77 Stockholm, Sweden
Nico P. Dantuma, E-mail: nico.dantuma{at}cmb.ki.se
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