PROPAGATION OF THE YEAST PRION-LIKE [PSI(-ENCODED POLYPEPTIDE-CHAIN RELEASE FACTOR()] DETERMINANT IS MEDIATED BY OLIGOMERIZATION OF THE SUP35)

The Sup35p protein of yeast Saccharomyces cerevisiae is a homologue of the polypeptide chain release factor 3 (eRF3) of higher eukaryotes, I t has been suggested that this protein may adopt a specific self-propa gating conformation, similar to mammalian prions, giving rise to the [ psi(+)] nonsense suppressor determinant, inherited in a non-Mendelian fashion. Here we present data confirming the prion-like nature of [psi (+)], We show that Sup35p molecules interact with each other through t heir N-terminal domains in [psi(+)], but not [psi(-)] cells, This inte raction is critical for [psi(+)] propagation, since its disruption lea ds to a loss of [psi(+)], Similarly to mammalian prions, in [psi(+)] c ells Sup35p forms high molecular weight aggregates, accumulating most of this protein, The aggregation inhibits Sup35p activity leading to a [psi(+)] nonsense-suppressor phenotype, N-terminally altered Sup35p m olecules are unable to interact with the [psi(+)] Sup35p isoform, rema in soluble and improve the translation termination in [psi(+)] strains , thus causing an antisuppressor phenotype, The overexpression of Hsp1 04p chaperone protein partially solubilizes Sup35p aggregates in the [ psi(+)] strain, also causing an antisuppressor phenotype, We propose t hat Hsp104p plays a role in establishing stable [psi(+)] inheritance b y splitting up Sup35p aggregates and thus ensuring equidistribution of the prion-like Sup35p isoform to daughter cells at cell divisions.