Chaperones that cure yeast artificial [PSI+] and their prion-specific effects

The [PSI+] nonsense-suppressor determinant of Saccharomyces cerevisiae resu lts from the ability of Sup35 (eRF3) translation termination factor to unde rgo prion-like aggregation [1]. Although this process is autocatalytic, in vivo it depends on the chaperone Hsp104, whose lack or overexpression can c ure [PSI+] [2]. Overproduction of the chaperone protein Ssb1 increased the [PSI+] curing by excess Hsp104, although it had no effect on its own, and e xcess chaperone protein Ssa1 protected [PSI+] against Hsp104 [3,4]. We used an artificial (PSIPS+] based on the Sup35 prion-forming domain from yeast Pichia methanolica [5] to find other prion-curing factors. Both [PSIPS+] an d [PSI+] have prion 'strains', differing in their suppressor efficiency and mitotic stability. We show that [PSIPS+] and a 'weak' strain of [PSI+] can be cured by overexpression of chaperones; Ssa1, Ssb1 and Ydj1. The ability of different chaperones; to cure [PSIPS+] showed significant prion strain specificity, which could be related to variation in Sup35 prion structure. Our results imply that homologs of these chaperones may be active against m ammalian prion and amyloid diseases.