title: Endoplasmic reticulum stress compromises the ubiquitin-proteasome system.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, The Medical Nobel Institute, Karolinska Institutet, PO Box 285, Von Eulers väg 3, S-171 77 Stockholm, Sweden.
authors.forename: Victoria
authors.initials: V
authors.lastname: Menéndez-Benito
authors.forename: Lisette G G C
authors.initials: LG
authors.lastname: Verhoef
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
mesh_terms: D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D011506:Proteins; D025801:Ubiquitin; D014415:Tunicamycin; D019284:Thapsigargin; D046988:Proteasome Endopeptidase Complex