title: Functions of yeast Hsp40 chaperone Sis1p dispensable for prion propagation but important for prion curing and protection from prion toxicity.
abstract: Replication of amyloid-based yeast prions [PSI(+)], [URE3], and [PIN(+)] depends on the protein disaggregation machinery that includes Hsp104, Hsp70, and Hsp40 molecular chaperones. Yet, overexpressing Hsp104 cures cells of [PSI(+)] prions. An Hsp70 mutant (Ssa1-21p) antagonizes propagation of [PSI(+)] in a manner resembling elevated Hsp104. The major cytosolic Hsp40 Sis1p is the only Hsp40 required for replication of these prions, but its role in [PSI(+)] curing is unknown. Here we find that all nonessential functional regions of Sis1p are dispensable for [PSI(+)] propagation, suggesting that other Hsp40's might provide Hsp40 functions required for [PSI(+)] replication. Conversely, several Sis1p functions were important for promoting antiprion effects of both Ssa1-21p and Hsp104, which implies a link between the antiprion effects of these chaperones and suggests that Sis1p is a specific Hsp40 important for [PSI(+)] curing. These contrasting findings suggest that the functions of Hsp104 that are important for propagation and elimination of [PSI(+)] are either distinct or specified by different Hsp40's. This work also uncovered a growth inhibition caused by [PSI(+)] when certain functions of Sis1p were absent, suggesting that Sis1p protects cells from cytotoxicity caused by [PSI(+)] prions.
authors.affiliation: Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0830, USA.
authors.forename: P Aaron
authors.initials: PA
authors.lastname: Kirkland
authors.forename: Michael
authors.initials: M
authors.lastname: Reidy
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Masison
mesh_terms: D015153:Blotting, Western; D015966:Gene Expression Regulation, Fungal; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011328:Prions; D011994:Recombinant Proteins; C070320:SIS1 protein, S cerevisiae; C090869:SSA3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae