The cellular concentration of the yeast Ure2p prion protein affects its propagation as a prion

The [URE3] yeast prion is a self-propagating inactive form of the Ure2p protein. We show here that Ure2p from the species Saccharomyces paradoxus (Ure2p(Sp)) can be efficiently converted into a prion form and propagate [URE3] when expressed in Saccharomyces cerevisiae at physiological level. We found however that Ure2p(Sp) overexpression prevents efficient prion propagation. We have compared the aggregation rate and propagon numbers of Ure2p(Sp) and of S. cerevisiae Ure2p (Ure2p(Sc)) in [URE3] cells both at different expression levels. Overexpression of both Ure2p orthologues accelerates formation of large aggregates but Ure2p(Sp) aggregates faster than Ure2p(Sc). Although the yeast cells that contain these large Ure2p aggregates do not transmit [URE3] to daughter cells, the corresponding crude extract retains the ability to induce [URE3] in wild-type [ure3-0] cells. At low expression level, propagon numbers are higher with Ure2p(Sc) than with Ure2p(Sp). Overexpression of Ure2p decreases the number of [URE3] propagons with Ure2p(Sc). Together, our results demonstrate that the concentration of a prion protein is a key factor for prion propagation. We propose a model to explain how prion protein overexpression can produce a detrimental effect on prion propagation and why Ure2p(Sp) might be more sensitive to such effects than Ure2p(Sc).