Abstract
Yeast prions are heritable amyloid aggregates of functional yeast proteins; their propagation to subsequent cell generations is dependent upon fragmentation of prion protein aggregates by molecular chaperone proteins. Mounting evidence indicates the J-protein Sis1 may act as an amyloid specificity factor, recognizing prion and other amyloid aggregates and enabling Ssa and Hsp104 to act in prion fragmentation. Chaperone interactions with prions, however, can be affected by variations in amyloid-core structure resulting in distinct prion variants or ‘strains’. Our genetic analysis revealed that Sis1 domain requirements by distinct variants of [PSI +] are strongly dependent upon overall variant stability. Notably, multiple strong [PSI +] variants can be maintained by a minimal construct of Sis1 consisting of only the J-domain and glycine/phenylalanine-rich (G/F) region that was previously shown to be sufficient for cell viability and [RNQ +] prion propagation. In contrast, weak [PSI +] variants are lost under the same conditions but maintained by the expression of an Sis1 construct that lacks only the G/F region and cannot support [RNQ +] propagation, revealing mutually exclusive requirements for Sis1 function between these two prions. Prion loss is not due to [PSI +]-dependent toxicity or dependent upon a particular yeast genetic background. These observations necessitate that Sis1 must have at least two distinct functional roles that individual prions differentially require for propagation and which are localized to the glycine-rich domains of the Sis1. Based on these distinctions, Sis1 plasmid-shuffling in a [PSI +]/[RNQ +] strain permitted J-protein-dependent prion selection for either prion. We also found that, despite an initial report to the contrary, the human homolog of Sis1, Hdj1, is capable of [PSI +] prion propagation in place of Sis1. This conservation of function is also prion-variant dependent, indicating that only one of the two Sis1-prion functions may have been maintained in eukaryotic chaperone evolution.
Highlights
Yeast prions are amyloid aggregates of functional yeast proteins that are both self-templating and heritable to daughter cells [1,2,3,4]
Sis1 functions as a co-chaperone protein with. Multiple neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob disease are associated with the accumulation of fibrous protein aggregates collectively termed ‘amyloid.’ In the baker’s yeast Saccharomyces cerevisiae, multiple proteins form intracellular amyloid aggregates known as yeast prions
Yeast prions minimally require a core set of chaperone proteins for stable propagation in yeast, including the J-protein Sis1, which appears to be required for the propagation of all yeast prions and functioning in each case
Summary
Yeast prions are amyloid aggregates of functional yeast proteins that are both self-templating and heritable to daughter cells [1,2,3,4]. The phenotype arises from Sup sequestration in prion aggregates and the strength of the nonsense suppression correlates to the lack of soluble Sup35 [10] Another yeast prion, first identified as the genetic element [Pin] for Psi inducibility, was later shown to be the aggregated form of the Rnq protein, hereafter called [RNQ+] for the high Asn (N) and Gln (Q) content of its prion forming domain [3,11,12]. Neither the deletion nor overexpression of Rnq, nor its aggregation in [RNQ+] cells results in any distinguishable phenotype beyond the tendency of [RNQ+] cells to spontaneously become [PSI+] at a greatly accelerated rate, the original denotation [PIN+] [3,12,13] While both Rnq and Sup are cytosolic and have prion-forming domains, they do not significantly intermix in aggregates, and so [RNQ+] and [PSI+] form independent and stable structures in vivo [14]
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