Monitoring Editor: Jonathan Chernoff The [URE3] yeast prion is a self-propagating inactive form of the Ure2p protein. We show here that Ure2p from the species Saccharomyces paradoxus (Ure2pSp) can be efficiently converted into a prion form and propagate [URE3] when expressed in S. cerevisiae at physiological level. We found however that Ure2pSp overexpression prevents efficient prion propagation. We have compared the aggregation rate and propagon numbers of Ure2pSp and of S. cerevisiae Ure2p (Ure2pSc) in [URE3] cells both at different expression levels. Overexpression of both Ure2p orthologues accelerates formation of large aggregates but Ure2pSp aggregates faster than Ure2pSc. While 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 Ure2pSc than with Ure2pSp.Overexpression of Ure2p decreases the number of [URE3] propagons with Ure2pSc. 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 Ure2pSp might be more sensitive to such effects than Ure2pSc.
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