Endoplasmic reticulum stress compromises the ubiquitin-proteasome system.
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.
Menéndez-Benito
Victoria
V
Department of Cell and Molecular Biology, The Medical Nobel Institute, Karolinska Institutet, PO Box 285, Von Eulers väg 3, S-171 77 Stockholm, Sweden.
Verhoef
Lisette G G C
LG
Masucci
Maria G
MG
Dantuma
Nico P
NP
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*
D011506:Proteins; D025801:Ubiquitin; D014415:Tunicamycin; D019284:Thapsigargin; D046988:Proteasome Endopeptidase Complex