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

• Published in: Molecular biology of the cell 2013-12, Vol.24 (23), p.3588-3602
• Main Authors: Wolfe, Katie J, Ren, Hong Yu, Trepte, Philipp, Cyr, Douglas M
• Format: Article
• Language: English
• Subjects: Amyloidogenic Proteins - toxicity; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Chemical Fractionation; Cytosol - drug effects; Cytosol - metabolism; Green Fluorescent Proteins - metabolism; Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - metabolism; Humans; Models, Biological; Molecular Weight; Mutant Proteins - metabolism; Nerve Tissue Proteins - toxicity; Prions - toxicity; Protein Binding - drug effects; Saccharomyces cerevisiae Proteins - metabolism; Saccharomyces cerevisiae Proteins - toxicity
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E13-06-0315

Conformational diseases are associated with the conversion of normal proteins into aggregation-prone toxic conformers with structures similar to that of β-amyloid. Spatial distribution of amyloid-like proteins into intracellular quality control centers can be beneficial, but cellular mechanisms for protective aggregation remain unclear. We used a high-copy suppressor screen in yeast to identify roles for the Hsp70 system in spatial organization of toxic polyglutamine-expanded Huntingtin (Huntingtin with 103Q glutamine stretch [Htt103Q]) into benign assemblies. Under toxic conditions, Htt103Q accumulates in unassembled states and speckled cytosolic foci. Subtle modulation of Sti1 activity reciprocally affects 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-monomeric red fluorescent protein 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.