Journal Article

Endoplasmic reticulum stress compromises the ubiquitin–proteasome system

Victoria Menéndez-Benito, Lisette G.G.C. Verhoef, Maria G. Masucci and Nico P. Dantuma

in Human Molecular Genetics

Volume 14, issue 19, pages 2787-2799
Published in print October 2005 | ISSN: 0964-6906
Published online August 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi312
Endoplasmic reticulum stress compromises the ubiquitin–proteasome system

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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.

Journal Article.  8016 words.  Illustrated.

Subjects: Genetics and Genomics

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