Selective accumulation of aggregation-prone proteasome substrates in response to proteotoxic stress.
Conditions causing an increase in misfolded or aberrant proteins can impair the activity of the ubiquitin/proteasome system (UPS). This observation is of particular interest, given the fact that proteotoxic stress is closely associated with a large variety of disorders. Although impairment of the UPS appears to be a general consequence of proteotoxic insults, the underlying mechanisms remain enigmatic. Here, we show that heat shock-induced proteotoxic stress resulted in conjugation of ubiquitin to detergent-insoluble protein aggregates, which coincided with reduced levels of free ubiquitin and impediment of ubiquitin-dependent proteasomal degradation. Interestingly, whereas soluble proteasome substrates returned to normal levels after a transient accumulation, the levels of an aggregation-prone substrate remained high even when the free ubiquitin levels were restored. Consistently, overexpression of ubiquitin prevented accumulation of soluble but not aggregation-prone substrates in thermally stressed cells. Notably, cells were also unable to resume degradation of aggregation-prone substrates after treatment with the translation inhibitor puromycin, indicating that selective accumulation of aggregation-prone proteins is a consistent feature of proteotoxic stress. Our data suggest that the failure of the UPS to clear aggregated proteins in the aftermath of proteotoxic stress episodes may contribute to the selective deposition of aggregation-prone proteins in conformational diseases.
Salomons
Florian A
FA
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Von Eulers Väg 3, S-17177, Stockholm, Sweden.
Menéndez-Benito
Victoria
V
Böttcher
Claudia
C
McCray
Brett A
BA
Taylor
J Paul
JP
Dantuma
Nico P
NP
D045744:Cell Line, Tumor; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011691:Puromycin / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D013696:Temperature; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D011691:Puromycin; D046988:Proteasome Endopeptidase Complex