Sensitivity of mammalian cells expressing mutant ubiquitin to protein-damaging agents
Open accessAbstract
There is convincing evidence from studies in yeast that a functional ubiquitin/proteasome pathway is required to degrade misfolded or oxidatively damaged proteins but for technical reasons, it has been difficult to perform comparable studies in mammalian cells. To investigate the possibility that the ubiquitin/proteasome pathway is cytoprotective for mammalian cells, we have introduced epitope-tagged wild-type ubiquitin or dominant-negative mutant versions of ubiquitin into mouse HT4 neuroblastoma cells. Cells expressing mutant versions of ubiquitin were found to be sensitive to cadmium, an agent that causes oxidative damage to cellular components, and to canavanine, an amino acid analog that generates misfolded proteins. The greatest sensitivity to canavanine was observed in cells expressing a mutant version of ubiquitin unable to support the formation of Lys(48) linkages. Substrates of the proteasome were found to accumulate in these cells, suggesting a general deficit in proteolysis. Our data suggest that defects in the ubiquitin-mediated proteolytic system predispose mammalian cells to the toxic effects of abnormal protein.
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Increased content with age of mutant forms of ubiquitin due to molecular misreading could be behind the inefficient clearance of polyubiquitinated proteins in aging.
“The increased content with age of mutant forms of ubiquitin due to molecular misreading could also be behind the inefficient clearance of polyubiquitinated proteins in aging (Tsirigotis et al., 2001).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Tsirigotis et al., 2001
The indexed passage labeled Abstract (page unavailable) reports that engineered K48R mutant ubiquitin-expressing cells accumulated high-molecular-weight ubiquitin conjugates and showed impaired proteolysis. It does not establish that mutant ubiquitin increases with age through molecular misreading or that this explains inefficient clearance in aging. (LLM, conf=0.86)
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Protein Homeostasis and Aging: the importance of exquisite quality control
Koga, H., Kaushik, S., & Cuervo, A. M. (2011) · Ageing research reviews · doi:10.1016/j.arr.2010.02.001 · Cited by 476 · see citing works
- Authors
- Tsirigotis, M., Zhang, M., Chiu, R. K., Wouters, B. G., & Gray, D. A.
- Affiliations
- University of Ottawa (CA)
- Corresponding author
- Gray, Douglas A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-12
- Volume
- 276
- Issue
- 49
- Pages
- 46073-46078
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2027966370
- Cited by
- 88
- References
- 0
- Citations by year
- 2025: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 2 · 2017: 2 · 2015: 2 · 2014: 5 · 2013: 4 · 2012: 6
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- ubiquitin, ubiquitin-proteasome system, cadmium toxicity, canavanine, misfolded proteins, oxidative protein damage, proteasome, proteasome substrates, neuroblastoma cells, cytoprotection, protein degradation
- MeSH terms
- Animals, Base Sequence, Cadmium, Canavanine, Cell Line, Cysteine Endopeptidases, Multienzyme Complexes, Mutation, Substrate Specificity, Transfection, DNA Primers, Ubiquitin, Proteasome Endopeptidase Complex
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