Identifying Endogenous Cellular Proteins Destabilizing the Propagation of Swi1 Prion upon Overproduction

(1) Background: Numerous prions exist in the budding yeast, including [SWI⁺], the prion form of Swi1—a subunit of the chromatin-remodeling complex SWI/SNF. Despite decades of research, the molecular mechanisms underlying prion initiation and propagation are not fully understood. In this study, we aimed to identify endogenous cellular proteins that destabilize [SWI⁺]. (2) Methods: We screened the MoBY-ORF 2.0 library for proteins that destabilize [SWI⁺] upon overproduction. We further explored the effects of the identified candidates against other yeast prions and analyzed their potential prion-curing mechanisms. (3) Results: Eighty-two [SWI⁺] suppressors were identified, and their effects were shown to be [SWI⁺]-specific. Interestingly, a few documented [SWI⁺] suppressors were not among the identified hits. Further experiments indicate that, for some of these [SWI⁺] suppressors, their overproduction, and thus their prion-curing activities, are regulated by environmental conditions. Bioinformatics analyses show that our identified [SWI⁺] suppressors are involved in diverse biological functions, with gene ontology term enrichments specifically for transcriptional regulation and translation. Competition for Swi1 monomers between [SWI⁺] and Swi1 interactors, including the SWI/SNF complex, is a potential prion-curing mechanism. (4) Conclusions: We identified a number of [SWI⁺]-specific suppressors that highlight unique features of [SWI⁺] in maintaining its self-perpetuating conformations.