Yeast prions are protein-based genetic elements found in the baker’s yeast Saccharomyces cerevisiae, most of which are amyloid aggregates that propagate by fragmentation and spreading of small, self-templating pieces called propagons. Fragmentation is carried out by molecular chaperones, specifically Hsp104, Hsp70, and Hsp40. Like other amyloid-forming proteins, amyloid-based yeast prions exhibit structural polymorphisms, termed “strains” in mammalian systems and “variants” in yeast, which demonstrate diverse phenotypes and chaperone requirements for propagation. Here, the known differential interactions between chaperone proteins and yeast prion variants are reviewed, specifically those of the yeast prions [PSI+], [RNQ+]/[PIN+], and [URE3]. For these prions, differences in variant-chaperone interactions (where known) with Hsp104, Hsp70s, Hsp40s, Sse1, and Hsp90 are summarized, as well as some interactions with chaperones of other species expressed in yeast. As amyloid structural differences greatly impact chaperone interactions, understanding and accounting for these variations may be crucial to the study of chaperones and both prion and non-prion amyloids.

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][4][5][6][7][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. Yeast prion structures are diverse and chaperone requirements are heterologousPrions can also form distinct amyloid structures (structural polymorphisms) called "strains" in mammalian systems and "variants" in yeast [2,9]. These polymorphisms dictate species transmission barriers and disease pathology in mammals, and the intensity of prion-associated phenotypes and stability in mitosis in yeast [9][10][11][12][13]. Recently, we and others have demonstrated that prion-chaperone requirements are heterogeneous and, in contrast to Hsp104 and Hsp70, which have general roles, J proteins appear to represent a prion-specific component of the prion propagation machinery. Most notable has been a direct demonstration that the persistence of distinct prion variants is dependent on the action of different molecular chaperones, of which here we will focus exclusively on the J-protein component. These findings suggest that distinct amyloid structures have unique features that are differentiable by chaperone proteins, revealing a previously unappreciated level of additional complexity that may be exploitable for therapeutic intervention.

Amyloid‐based yeast prions are heritable aggregates of misfolded protein that can be passed on to daughter cells following fragmentation by chaperone proteins including Hsp70, Hsp104, and the Hsp40 Sis1. Yeast prions usually exhibit an amyloid structure, forming cross‐beta sheets of protein sections known as the prion‐forming domain, or PrD. In vivo, long tracts of glutamine have been shown to form amyloid structures. Previously Alexandrov et al. created a set of polyQ sequences with a single heterologous amino acid interspersed every fifth residue (QQQXQ), fused to the MC regions of yeast Sup35 (responsible for the prion [PSI+]) and expressed in a sup35‐ΔN strain of Saccharomyces cerevisiae. These polyQX sequences replace the PrD of Sup35, and form amyloid aggregates in vivo that propagate in an Hsp104‐dependent manner. Here we report our efforts to test the J‐protein chaperone requirements of these aggregates, first by repressing levels of Sis1 to determine if any polyQX aggregates are maintained without Sis1. Preliminary results suggest several QX constructs are dependent upon Sis1 for propagation, demonstrating that these aggregates propagate in an Hsp40/Hsp70‐dependent manner. Subsequent replacement of wild‐type Sis1 expression with several well‐studied Sis1 variants will allow the determination of the importance of specific regions of Sis1 for the propagation of these aggregates. We anticipate that this line of investigation will provide significant insight into the ways in which amino acid content of a PrD affects the interaction of the resulting prion with chaperone proteins.Support or Funding InformationThis work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R15GM110606. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.