title: Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress.
abstract: 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.
authors.affiliation: Department of Biology, Stanford University, Stanford, California 94305, USA.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Escusa-Toret
authors.forename: Willianne I M
authors.initials: WI
authors.lastname: Vonk
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
mesh_terms: D001383:Azetidinecarboxylic Acid / Q000633:toxicity; D060833:Cellular Microenvironment / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity; D006358:Hot Temperature; D018832:Molecular Chaperones / Q000378:metabolism*; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D018832:Molecular Chaperones; D000431:Ethanol; D001383:Azetidinecarboxylic Acid
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