Abstract
Baker’s yeast Saccharomyces cerevisiae is an important model organism that is applied to study various aspects of eukaryotic cell biology. Prions in yeast are self-perpetuating heritable protein aggregates that can be leveraged to study the interaction between the protein quality control (PQC) machinery and misfolded proteins. More than ten prions have been identified in yeast, of which the most studied ones include [PSI+], [URE3], and [PIN+]. While all of the major molecular chaperones have been implicated in propagation of yeast prions, many of these chaperones differentially impact propagation of different prions and/or prion variants. In this review, we summarize the current understanding of the life cycle of yeast prions and systematically review the effects of different chaperone proteins on their propagation. Our analysis clearly shows that Hsp40 proteins play a central role in prion propagation by determining the fate of prion seeds and other amyloids. Moreover, direct prion-chaperone interaction seems to be critically important for proper recruitment of all PQC components to the aggregate. Recent results also suggest that the cell asymmetry apparatus, cytoskeleton, and cell signaling all contribute to the complex network of prion interaction with the yeast cell.
Highlights
In addition to the main chaperone systems described above, additional pathways are important for prion propagation and are directly or indirectly involved in regulation of protein quality control (PQC) activity
Changes in the Sis1 domain structure have slightly different impact on Hsp104-mediated curing of [PSI+ ]: deletion of the C-proximal substrate-binding domain (CTD) of Sis1 or the dimerization domain located at the very end of the protein substantially decreases levels of prion curing by elevated HSP104 expression [44]
The first model implies that tight binding of Sis1 or Apj1 to prion seeds may prevent efficient recruitment of Hsp70-Ssa to aggregates, which in turn increases the possibility of direct interaction between Hsp104 NTD and a propagon
Summary
Over the recent two decades, researchers have discovered more than ten yeast prions (reviewed in [9,14]). The amount of soluble Sup in the cell decreases due to its inclusion into the aggregates, causing translational stop codon readthrough [24] Another well-studied prion, [URE3], is formed by the Ure protein which is a nitrogen catabolite repression regulator [16]. The structural diversity of the amyloid cores drives the phenotypic diversity of yeast prion strains (variants) Such prion variants are characterized by different strength of phenotypic manifestation (e.g., levels of nonsense suppression), amount of soluble protein in the cell, and size of amyloid aggregates [32,33]. Arrowheads point to locations of most notable mutations affecting prion propagation or prion curing by excess Hsp104
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