Chaperone functional specificity promotes yeast prion diversity

While prions are protein-based infectious agents, yeast prions are protein-based genetic elements of the baker’s yeast Saccharomyces cerevisiae [1]. Most yeast prions are amyloid protein aggregates that spread during mitosis through the cytosolic transmission of small, self-templating pieces called propagons. Propagons continue to recruit free protein monomers, perpetuating the prion phenotype in daughter cells [2]. Similar to the reliance of viruses upon host replication machinery, propagation of yeast prions to subsequent cell generations is dependent upon the fragmentation of aggregates by a core set of cellular chaperone proteins to create new propagons. The following three proteins make up the core “prion–chaperone machinery”: the hexameric disaggregase Hsp104, the cytosolic Hsp70 Ssa, and the Hsp40 (also and hereafter called a “J protein”) Sis1 [2]. Propagon generation is dependent upon the severing of amyloid fibers by Hsp104, which requires the upstream action of the Hsp70 Ssa and Sis1 to first bind to amyloids and unfold a portion of the protein, either exposing it or directly transferring it to Hsp104 [3–8]. Here, we will focus on the role of J proteins in promoting the propagation of a wide variety of yeast prions with the aim of better understanding how amyloid diversity is dependent on diverse chaperone activities.