Differential effects of chaperones on yeast prions: CURrent view

Abstract

Endogenous yeast amyloids that control heritable traits and are frequently used as models for human amyloid diseases are termed yeast prions. Yeast prions, including the best studied ones ([PSI ] and [URE3]), propagate via intimate interactions with molecular chaperones. Different yeast prions exhibit differential responses to changes in levels, functionality or localization of the components of chaperone machinery. Here, we provide additional data confirming differential effects of chaperones (and specifically, Hsp40s) on yeast prions and summarize current knowledge of the mechanisms underlying chaperone specificities. Contrary to frequent statements in literature, overproduction of the Hsp104 chaperone antagonizes both [PSI] and [URE3] prions, while overproduction of the Hsp70-Ssa1 chaperone antagonizes [URE3] prion only in some, but not in all strains. Recently, we demonstrated that the relocalization of a fraction of the Hsp40 chaperone Sis1 from the cytosol to the nucleus by the chaperone-sorting factor Cur1 exhibits opposite effects on [PSI ] and [URE3] prions. We suggest that the response of prions to changes in Sis1 localization represents a combination of the effects of Sis1 shortage on fragmentation of prion aggregates and on malpartition of prion aggregates during a cell division. Differences in sensitivity of prion fragmentation to Sis1 and in relative inputs of fragmentation and malpartition in prion propagation result in opposite effects of Sis1 relocalization on [PSI] and [URE3].

Variant‐specific and reciprocal Hsp40 functions in Hsp104‐mediated prion elimination

“…A recent review by Chernoff and coworkers considers both models of Hsp104‐mediated curing together with the notion of Hsp104‐mediated curing as an antiprion system, integrating those ideas with the considerable data that exists regarding the sensitivity of [ PSI + ] and [ URE3 ] to ectopic chaperone expression (Matveenko et al ., ). Again, most relevant to this work was their focus on the impact of J‐proteins on these prions.…”

“…Of the multiple models for Hsp104‐mediated curing that have been proposed, two have been significantly debated in the recent literature: malpartitioning of [ PSI + ] aggregates during cell division (Ness et al ., ; Cox and Tuite, ; Matveenko et al ., ) and the trimming of prion aggregates followed by eventual destruction of prion cores (Park et al ., ; Zhao et al ., ; Greene et al ., ). In our opinion, our data reported here do not significantly support one model over the other, largely because neither model (nor previously favored models for Hsp104 curing) explicitly addresses the requirement for J‐proteins in the process.…”

“…We find their model compelling and can now add to it with our own contributions to bring a degree of symmetry to the model (Fig. , see Matveenko et al ., for full model with alternative emphasis on the effects of Cur1, omitted here for clarity). In short, they proposed that [ PSI + ] and [ URE3 ] differ by their reciprocal sensitivities to two distinct J‐protein‐mediated processes that are always occurring: Hsp104‐mediated prion fragmentation to produce propagons and Hsp104‐mediated curing.…”

“…To date, the mechanism by which Hsp104 cures [ PSI + ] specifically remains the subject of significant debate in literature as numerous distinct models have been proposed (Winkler et al ., ; Helsen and Glover, b, Park et al ., ; Ness et al ., ; Zhao et al ., ; Cox and Tuite, ; Greene et al ., ; Matveenko et al ., ). In just the past year, significant evidence for two, largely conflicting models has been presented (Ness et al ., ; Zhao et al ., ).…”

“…In just the past year, significant evidence for two, largely conflicting models has been presented (Ness et al ., ; Zhao et al ., ). One asserts that Hsp104 cures [ PSI + ] by causing malpartitioning of propagons during cell division (Liebman and Chernoff, ; Ness et al ., ; Cox and Tuite, ; Matveenko et al ., ). Malpartitioning is proposed to occur due to Hsp70‐independent binding of Hsp104 to [ PSI + ] aggregates, followed by the anchoring of aggregates to a cellular structure (likely a cytoskeletal element) in a process that requires Hsp104 ATPase activity (Ness et al ., ; Cox and Tuite, ).…”