Misfolded proteins partition between two distinct quality control compartments
Open accessAbstract
The accumulation of misfolded proteins in intracellular amyloid inclusions, typical of many neurodegenerative disorders including Huntington's and prion disease, is thought to occur after failure of the cellular protein quality control mechanisms. Here we examine the formation of misfolded protein inclusions in the eukaryotic cytosol of yeast and mammalian cell culture models. We identify two intracellular compartments for the sequestration of misfolded cytosolic proteins. Partition of quality control substrates to either compartment seems to depend on their ubiquitination status and aggregation state. Soluble ubiquitinated misfolded proteins accumulate in a juxtanuclear compartment where proteasomes are concentrated. In contrast, terminally aggregated proteins are sequestered in a perivacuolar inclusion. Notably, disease-associated Huntingtin and prion proteins are preferentially directed to the perivacuolar compartment. Enhancing ubiquitination of a prion protein suffices to promote its delivery to the juxtanuclear inclusion. Our findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease.
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Because small HSPs can bind abnormal proteins multivalently, they might seed and concentrate aggregate material.
“Having multi-valent binding ability for aberrant proteins, the small HSPs may act to seed and concentrate aggregate material, consistent with findings in vivo (Escusa-Toret et al., 2013; Kaganovich et al., 2008; Specht et al., 2011) and in vitro (Haslbeck et al., 2005; Jiao et al., 2005).”
From Widespread Proteome Remodeling and Aggregation in Aging C. elegans (2015) · cites this paper as Kaganovich et al., 2008
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RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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- Authors
- Kaganovich, D., Kopito, R., & Frydman, J.
- Affiliations
- Stanford University (US)
- Corresponding author
- Frydman, Judith
- Venue
- Nature
- Published
- 2008-08
- Volume
- 454
- Issue
- 7208
- Pages
- 1088-1095
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2746971
- OpenAlex
- W1967025628
- Cited by
- 932
- References
- 57
- Citations by year
- 2026: 24 · 2025: 29 · 2024: 41 · 2023: 47 · 2022: 40 · 2021: 52 · 2020: 55 · 2019: 53 · 2018: 54 · 2017: 76 · 2016: 74 · 2015: 65 · 2014: 71 · 2013: 59 · 2012: 58
- FWCI
- 18.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM056433)
- National Institute of Neurological Disorders and Stroke (R01NS042842)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- protein misfolding, protein quality control, ubiquitination, proteasome, protein aggregation, huntingtin, prion protein, autophagy, neurodegenerative diseases, yeast, mammalian cells
- MeSH terms
- Ubiquitin-Conjugating Enzyme UBC9, Cytosol, HeLa Cells, Humans, Prions, Proteins, Saccharomyces cerevisiae, Solubility, Protein Folding, Ubiquitin-Conjugating Enzymes, Proteasome Endopeptidase Complex, Von Hippel-Lindau Tumor Suppressor Protein, Ubiquitination
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