Abstract
Prions are proteins that can adopt different infectious conformations known as "strains" or "variants," each with a distinct, epigenetically inheritable phenotype. Mechanisms by which prion variants are determined remain unclear. Here we use the Saccharomyces cerevisiae prion Rnq1p/[PIN(+)] as a model to investigate the effects of chaperone proteins upon prion variant determination. We show that deletion of specific chaperone genes alters [PIN(+)] variant phenotypes, including [PSI(+)] induction efficiency, Rnq1p aggregate morphology/size and variant dominance. Mating assays demonstrate that gene deletion-induced phenotypic changes are stably inherited in a non-Mendelian manner even after restoration of the deleted gene, confirming that they are due to a bona fide change in the [PIN(+)] variant. Together, our results demonstrate a role for chaperones in regulating the prion variant complement of a cell.
Highlights
Prion proteins adopt different conformations, known as variants, each with a distinct phenotype
Deletion of SBA1 in the [PINϩ]medium and [PINϩ]high backgrounds decreased the efficiency of [PSIϩ] induction to levels matching those of the wild-type [PINϩ]low strain but did not significantly decrease the efficiency of [PSIϩ] induction when deleted in the [PINϩ]low strain
When we characterized the [PINϩ] variant of our yeast two-hybrid strain (HF7c) by semi-denaturing detergent-agarose gel electrophoresis (SDD-AGE) and localization of Rnq1-GFP, we found HF7c to be [pinϪ], suggesting that the interactions we detected occur when Rnq1p is in its non-prion conformation
Summary
Prion proteins adopt different conformations, known as variants, each with a distinct phenotype. We show that deletion of specific chaperone genes alters [PIN؉] variant phenotypes, including [PSI؉] induction efficiency, Rnq1p aggregate morphology/size and variant dominance. Some [PINϩ] variants include [PINϩ]low, [PINϩ]medium, and [PINϩ]high, each named for its respective [PSIϩ] induction efficiency [16] Another [PINϩ] variant-linked phenotype is observed when GFP-tagged Rnq1p is overproduced in vivo [22]. [PINϩ]high strains form multiple Rnq1-GFP foci per cell, whereas [PINϩ]medium and [PINϩ]low strains generally form only a single Rnq1-GFP focus Another phenotypic difference between [PINϩ] variants is the size and stability of their amyloid aggregates. [PINϩ]high is dominant over [PINϩ]medium, which is in turn dominant over [PINϩ]low [16] These multiple, distinct phenotypes make [PINϩ] an ideal model system with which to study the etiology of prion variants. Our findings provide evidence that chaperones can affect established prion variants and highlight a potential role for chaperones in regulating prion-linked phenotypes through their modulation of prion variants
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