Hsp104 disaggregase at normal levels cures many [] prion variants in a process promoted by Sti1p, Hsp90, and Sis1p.

Overproduction or deficiency of many chaperones and other cellular components cure the yeast prions [] (formed by Sup35p) or [] (based on Ure2p). However, at normal expression levels, Btn2p and Cur1p eliminate most newly arising [] variants but do not cure [], even after overexpression. Deficiency or overproduction of Hsp104 cures the [] prion. Hsp104 deficiency curing is a result of failure to cleave the Sup35p amyloid filaments to make new seeds, whereas Hsp104 overproduction curing occurs by a different mechanism. Hsp104(T160M) can propagate [], but cannot cure it by overproduction, thus separating filament cleavage from curing activities. Here we show that most [] variants arising spontaneously in an strain are cured by restoration of just normal levels of the WT Hsp104. Both strong and weak [] variants are among those cured by this process. This normal-level Hsp104 curing is promoted by Sti1p, Hsp90, and Sis1p, proteins previously implicated in the Hsp104 overproduction curing of []. The [] prion arises in cells at more than 10-fold the frequency in WT cells. The curing activity of Hsp104 thus constitutes an antiprion system, culling many variants of the [] prion at normal Hsp104 levels.