Curing of [PSI⁺] by Hsp104 Overexpression: Clues to solving the puzzle

The yeast [PSI⁺] prion, which is the amyloid form of Sup35, has the unusual property of being cured not only by the inactivation of, but also by the overexpression of Hsp104. Even though this latter observation was made more than two decades ago, the mechanism of curing by Hsp104 overexpression has remained controversial. This question has been investigated in depth by our laboratory by combining live cell imaging of GFP-labeled Sup35 with standard plating assays of yeast overexpressing Hsp104. We will discuss why the curing of [PSI⁺] by Hsp104 overexpression is not compatible with a mechanism of either inhibition of severing of the prion seeds or asymmetric segregation of the seeds. Instead, our recent data (J. Biol. Chem. 292:8630-8641) indicate that curing is due to dissolution of the prion seeds, which in turn is dependent on the trimming activity of Hsp104. This trimming activity decreases the size of the seeds by dissociating monomers from the fibers, but unlike Hsp104 severing activity, it does not increase the number of prion seeds. Finally, we will discuss the other factors that affect the curing of [PSI⁺] by Hsp104 overexpression and how these factors may relate to the trimming activity of Hsp104.