Endoplasmic reticulum stress compromises the ubiquitin–proteasome system

• Published in: Human molecular genetics 2005-10, Vol.14 (19), p.2787-2799
• Main Authors: Menéndez-Benito, Victoria, Verhoef, Lisette G.G.C., Masucci, Maria G., Dantuma, Nico P.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cell Nucleus - metabolism; Cells, Cultured; Cytosol - metabolism; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Medicin och hälsovetenskap; Mice; Mice, Transgenic; Molecular and cellular biology; Proteasome Endopeptidase Complex - metabolism; Protein Folding; Proteins - metabolism; Thapsigargin - pharmacology; Tunicamycin - pharmacology; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi312

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.