Yeast Short-Lived Actin-Associated Protein Forms a Metastable Prion in Response to Thermal Stress

Self-perpetuating ordered protein aggregates (amyloids and prions) are associated with a variety of neurodegenerative disorders. Although environmental agents have been linked to certain amyloid diseases, the molecular basis of their action remains unclear. We have employed endogenous yeast prions as a model system to study environmental control of amyloid formation. A short-lived actin-associated yeast protein Lsb2 can trigger prion formation by other proteins in a mode regulated by the cytoskeleton and ubiquitin-dependent processes. Here, we show that such a heterologous prion induction is due to the ability of Lsb2 to form a transient prion state, generated in response to thermal stress. Evolutionary acquisition of prion-inducing activity by Lsb2 is traced to a single amino acid change, coinciding with the acquisition of thermotolerance in the Saccharomyces yeast lineage. This raises the intriguing possibility that the transient prion formation could aid in functioning of Lsb2 at higher temperatures. [Display omitted] •Yeast protein Lsb2 forms a metastable prion inducing formation of other prions•Thermal stress triggers formation of the metastable prion state of Lsb2•Lsb2 has acquired prion activity in evolution due to a single amino acid change•This change coincides with yeast adaptation to higher growth temperatures Prions are transmissible protein aggregates. Chernova et al. show that a transient prion of yeast short-lived cytoskeletal protein Lsb2 is triggered by thermal stress and induces other prions. Evolutionary acquisition of prion-inducing activity by Lsb2 is traced to a single amino acid substitution, coinciding with yeast adaptation to higher temperatures.