Heterologous gln/asn-rich proteins impede the propagation of yeast prions by altering chaperone availability.
Prions are self-propagating conformations of proteins that can cause heritable phenotypic traits. Most yeast prions contain glutamine (Q)/asparagine (N)-rich domains that facilitate the accumulation of the protein into amyloid-like aggregates. Efficient transmission of these infectious aggregates to daughter cells requires that chaperones, including Hsp104 and Sis1, continually sever the aggregates into smaller "seeds." We previously identified 11 proteins with Q/N-rich domains that, when overproduced, facilitate the de novo aggregation of the Sup35 protein into the [PSI(+)] prion state. Here, we show that overexpression of many of the same 11 Q/N-rich proteins can also destabilize pre-existing [PSI(+)] or [URE3] prions. We explore in detail the events leading to the loss (curing) of [PSI(+)] by the overexpression of one of these proteins, the Q/N-rich domain of Pin4, which causes Sup35 aggregates to increase in size and decrease in transmissibility to daughter cells. We show that the Pin4 Q/N-rich domain sequesters Hsp104 and Sis1 chaperones away from the diffuse cytoplasmic pool. Thus, a mechanism by which heterologous Q/N-rich proteins impair prion propagation appears to be the loss of cytoplasmic Hsp104 and Sis1 available to sever [PSI(+)].
Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
Zi
Z
Yang
Joo Y
JY
Hong
Irina L
IL
Derkatch
Susan W
SW
Liebman
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000235:genetics / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010454:Peptide Termination Factors; D011328:Prions; C070320:SIS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005973:Glutamine; C070972:HsP104 protein, S cerevisiae; D001216:Asparagine