Hsp104 disaggregase at normal levels cures many [<i>PSI</i>⁺] prion variants in a process promoted by Sti1p, Hsp90, and Sis1p

Abstract

Overproduction or deficiency of many chaperones and other cellular components cure the yeast prions [<i>PSI</i>⁺] (formed by Sup35p) or [<i>URE3</i>] (based on Ure2p). However, at normal expression levels, Btn2p and Cur1p eliminate most newly arising [<i>URE3</i>] variants but do not cure [<i>PSI</i>⁺], even after overexpression. Deficiency or overproduction of Hsp104 cures the [<i>PSI</i>⁺] 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 [<i>PSI</i>⁺], but cannot cure it by overproduction, thus separating filament cleavage from curing activities. Here we show that most [<i>PSI</i>⁺] variants arising spontaneously in an <i>hsp104(T160M)</i> strain are cured by restoration of just normal levels of the WT Hsp104. Both strong and weak [<i>PSI</i>⁺] 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 [<i>PSI</i>⁺]. The [<i>PSI</i>⁺] prion arises in <i>hsp104(T160M)</i> 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 [<i>PSI</i>⁺] prion at normal Hsp104 levels.