title: Human J-protein DnaJB6b Cures a Subset of Saccharomyces cerevisiae Prions and Selectively Blocks Assembly of Structurally Related Amyloids.
abstract: Human chaperone DnaJB6, an Hsp70 co-chaperone whose defects cause myopathies, protects cells from polyglutamine toxicity and prevents purified polyglutamine and Aβ peptides from forming amyloid. Yeast prions [URE3] and [PSI(+)] propagate as amyloid forms of Ure2 and Sup35 proteins, respectively. Here we find DnaJB6-protected yeast cells from polyglutamine toxicity and cured yeast of both [URE3] prions and weak variants of [PSI(+)] prions but not strong [PSI(+)] prions. Weak and strong variants of [PSI(+)] differ only in the structural conformation of their amyloid cores. In line with its anti-prion effects, DnaJB6 prevented purified Sup35NM from forming amyloids at 37 °C, which produce predominantly weak [PSI(+)] variants when used to infect yeast, but not at 4 °C, which produces mostly strong [PSI(+)] variants. Thus, structurally distinct amyloids composed of the same protein were differentially sensitive to the anti-amyloid activity of DnaJB6 both in vitro and in vivo. These findings have important implications for strategies using DnaJB6 as a target for therapy in amyloid disorders.
authors.affiliation: From the Laboratory of Biochemistry and Genetics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Michael
authors.initials: M
authors.lastname: Reidy
authors.affiliation: From the Laboratory of Biochemistry and Genetics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Ruchika
authors.initials: R
authors.lastname: Sharma
authors.affiliation: From the Laboratory of Biochemistry and Genetics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Brittany-Lee
authors.initials: BL
authors.lastname: Roberts
authors.affiliation: From the Laboratory of Biochemistry and Genetics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 danielmas@helix.nih.gov.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Masison
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae
keywords: DnaJB6; amyloid; chaperone; heat shock protein (HSP); prion; yeast