Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress
Open accessAbstract
The extensive links between proteotoxic stress, protein aggregation and pathologies ranging from ageing to neurodegeneration underscore the importance of understanding how cells manage protein misfolding. Using live-cell imaging, we determine the fate of stress-induced misfolded proteins from their initial appearance until their elimination. Upon denaturation, misfolded proteins are sequestered from the bulk cytoplasm into dynamic endoplasmic reticulum (ER)-associated puncta that move and coalesce into larger structures in an energy-dependent but cytoskeleton-independent manner. These puncta, which we name Q-bodies, concentrate different misfolded and stress-denatured proteins en route to degradation, but do not contain amyloid aggregates, which localize instead to the insoluble protein deposit compartment. Q-body formation and clearance depends on an intact cortical ER and a complex chaperone network that is affected by rapamycin and impaired during chronological ageing. Importantly, Q-body formation enhances cellular fitness during stress. We conclude that spatial sequestration of misfolded proteins in Q-bodies is an early quality control strategy occurring synchronously with degradation to clear the cytoplasm of potentially toxic species.
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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 Escusa-Toret et al., 2013
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- Authors
- Escusa-Toret, S., Vonk, W. I. M., & Frydman, J.
- Affiliations
- Stanford University (US)
- Corresponding author
- Frydman, Judith
- Venue
- Nature Cell Biology
- Published
- 2013-09-15
- Volume
- 15
- Issue
- 10
- Pages
- 1231-1243
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4121856
- OpenAlex
- W2092986760
- Cited by
- 321
- References
- 65
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 26 · 2023: 30 · 2022: 16 · 2021: 30 · 2020: 35 · 2019: 27 · 2018: 29 · 2017: 24 · 2016: 20 · 2015: 36 · 2014: 23 · 2013: 4
- FWCI
- 12.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (PN2EY016525)
- National Institute of General Medical Sciences (R37GM056433, R01GM056433)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- protein misfolding, ER-associated degradation, chaperone network, proteotoxic stress, protein aggregation, endoplasmic reticulum, proteasome, chronological aging, rapamycin, cell fitness, protein quality control, amyloid aggregates, inclusion bodies
- MeSH terms
- Ethanol, Azetidinecarboxylic Acid, Endoplasmic Reticulum, Hot Temperature, Saccharomyces cerevisiae, Stress, Physiological, Signal Transduction, Protein Folding, Molecular Chaperones, Protein Transport, Cellular Microenvironment
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