Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity

Abstract

Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as ‘strains’ in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called ‘variants’, dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI+] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1.1 Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored.

To CURe or not to CURe? Differential effects of the chaperone sorting factor Cur1 on yeast prions are mediated by the chaperone Sis1

“…data), a process that, according to Ness et al ., , depends on polymer mispartitioning. Consistently, various non‐lethal mutations in Sis1 as well as substitution of Sis1 by its mammalian homolog counteract loss of [ PSI + ] in the presence of excess Hsp104 (Kirkland et al ., ; Sporn and Hines, ). Excess Sis1, as well as depletion of Ydj1, also increases destabilization of [ PSI + ] by the mutant Ssa1‐21 protein (Jones and Masison, ; Kirkland et al ., ), which was proposed to occur by the same mechanism as curing by excess Hsp104 (Reidy and Masison, ).…”

Potential mechanisms and implications for the formation of tau oligomeric strains

“…There may be diversity by brain region as well as by cell type as different environmental conditions including pH(Sneideris et al , 2015, Verasdonck et al , 2015) and temperature(Tanaka et al , 2006) could lead to conformational changes. The impact of interactions with chaperones, as well as post-translational modifications are also important areas of exploration as the formation of amyloid strains has been shown to depend on variability of chaperone interaction(Sporn and Hines, 2015) and tau is known to interact with a number of different chaperones that affect its aggregation(Petrucelli et al , 2004, Dickey et al , 2006). Additionally, differences in conformers or strains may characterize different tauopathies, explaining pathological differences in tau diseases.…”

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

“…In addition to its role in prion fragmentation for stable propagation, Sis1 is essential for [ PSI + ] curing by Hsp104 overexpression, as depletion or mutation of Sis1 antagonizes curing whereas Sis1 overexpression accelerates it (Kryndushkin et al ., ; Kirkland et al ., ; Newnam et al ., ; Kiktev et al ., ; Sporn and Hines, ). However, despite significant work on the role of Sis1 in prion propagation, its role in [ PSI + ] curing via Hsp104 overabundance is much less clear.…”