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The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins

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Item Type:Article
Title:The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins
Creators Name:Wolfe, K.J. and Ren, H.Y. and Trepte, P. and Cyr, D.M.
Abstract:Conformational diseases are associated with the conversion of normal proteins into aggregation prone toxic conformers with structures similar to {beta}-amyloid. Spatial distribution of amyloid-like proteins into intracellular quality control centers can be beneficial, but cellular mechanisms for protective aggregation remain unclear. A high-copy suppressor screen in yeast was utilized to identify roles for the Hsp70 system in spatial organization of toxic polyglutamine expanded Huntingtin (Htt103Q) into benign assemblies. Under toxic conditions, Htt103Q accumulates in unassembled states and speckled cytosolic foci. Subtle modulation of Sti1 activity reciprocally impacts Htt toxicity and the packaging of Htt103Q into foci. Loss of Sti1 exacerbates Htt toxicity and hinders foci formation, whereas elevation of Sti1 suppresses Htt toxicity while organizing small Htt103Q foci into larger assemblies. Sti1 also suppresses cytotoxicity of the glutamine-rich yeast prion [RNQ+] while reorganizing speckled Rnq1-mRFP into distinct foci. Sti1 inducible foci are perinuclear and contain proteins that are bound by the amyloid indicator dye thioflavin-T. Sti1 is an Hsp70 cochaperone that regulates the spatial organization of amyloid-like proteins in the cytosol and thereby buffers proteotoxicity caused by amyloid-like proteins.
Keywords:Amyloidogenic Proteins, Biological Models, Cell Nucleus, Chemical Fractionation, Cytosol, Green Fluorescent Proteins, HSP40 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Heat-Shock Proteins, Molecular Weight, Mutant Proteins, Nerve Tissue Proteins, Prions, Protein Binding, Saccharomyces cerevisiae Proteins
Source:Molecular Biology of the Cell
ISSN:1059-1524
Publisher:American Society for Cell Biology (U.S.A.)
Volume:24
Number:23
Page Range:3588-3602
Date:December 2013
Official Publication:https://doi.org/10.1091/mbc.E13-06-0315
PubMed:View item in PubMed

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