title: Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.
abstract: Cross-beta fibrous protein aggregates (amyloids and amyloid-based prions) are found in mammals (including humans) and fungi (including yeast), and are associated with both diseases and heritable traits. The Hsp104/70/40 chaperone machinery controls propagation of yeast prions. The Hsp70 chaperones Ssa and Ssb show opposite effects on [PSI(+)], a prion form of the translation termination factor Sup35 (eRF3). Ssb is bound to translating ribosomes via ribosome-associated complex (RAC), composed of Hsp40-Zuo1 and Hsp70-Ssz1. Here we demonstrate that RAC disruption increases de novo prion formation in a manner similar to Ssb depletion, but interferes with prion propagation in a manner similar to Ssb overproduction. Release of Ssb into the cytosol in RAC-deficient cells antagonizes binding of Ssa to amyloids. Thus, propagation of an amyloid formed because of lack of ribosome-associated Ssb can be counteracted by cytosolic Ssb, generating a feedback regulatory circuit. Release of Ssb from ribosomes is also observed in wild-type cells during growth in poor synthetic medium. Ssb is, in a significant part, responsible for the prion destabilization in these conditions, underlining the physiological relevance of the Ssb-based regulatory circuit.
authors: School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg, Russia.
authors: Denis A
authors: DA
authors: Kiktev
authors: Mikhail M
authors: MM
authors: Melomed
authors: Caroline D
authors: CD
authors: Lu
authors: Gary P
authors: GP
authors: Newnam
authors: Yury O
authors: YO
authors: Chernoff
mesh_terms: D005246:Feedback; D018832:Molecular Chaperones / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000096:biosynthesis*; D011328:Prions / Q000096:biosynthesis*; D012270:Ribosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis*
chemical_list: D018832:Molecular Chaperones; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins
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