Hsp104 drives "protein-only" positive selection of Sup35 prion strains encoding strong [PSI(+)]

Structurally distinct, self-templating prion "strains" can encode distinct phenotypes and amplify at different rates depending upon the environment. Indeed, prion strain ensembles can evolve in response to environmental challenges, which makes them highly challenging drug targets. It is not understood how the proteostasis network amplifies one prion strain at the expense of another. Here, we demonstrate that Hsp104 remodels the distinct intermolecular contacts of different synthetic Sup35 prion strains in a way that selectively amplifies prions encoding strong [PSI(+)] and simultaneously eliminates prions encoding weak [PSI(+)]. Hsp104 has reduced ability to fragment prions encoding weak [PSI(+)], but readily converts them to nontemplating forms. By contrast, Hsp104 readily fragments prions encoding strong [PSI(+)], but has reduced ability to eliminate their infectivity. Thus, we illuminate direct mechanisms underpinning how the proteostasis network can drive prion strain selection.