Prion formation in yeast is influenced by alterations of the ubiquitin proteolysis

Abstract

Prions are infectious aggregated proteins that cause neurodegenerative diseases in mammals and transmit heritable traits in yeast. De novo appearance of a yeast prion is facilitated by an increase in the concentration of the same protein or by the presence of aggregates of a different QN‐rich protein. Since levels of protein in the cell are controlled at least in part by ubiquitin proteasome system (UPS), we investigated the role of UPS in maintenance of a prion isoform of the yeast translation termination factor Sup35. Deletion of the ubiquitin‐conjugating enzyme Ubc4 increased de novo prion formation and antagonized prion elimination by the disaggregating chaperone Hsp104. Although levels of Sup35 protein were not affected by this UPS alteration, levels of the QN‐rich protein Pin3 were increased. We confirmed that overexpression of Pin3 protein stimulates prion formation by Sup35 and demonstrated that Pin3 is present in the cell in the ubiquitinated form. Prevention of Pin3 ubiquitination by mutation has an effect on protein stability, cellular localization and aggregation. Our data suggest that UPS can regulate prion formation via modulation of QN‐rich proteins in the yeast model.(Supported by grant GM30308 from NIH)