Variant-specific and reciprocal Hsp40 functions in Hsp104-mediated prion elimination.

The amyloid-based prions of Saccharomyces cerevisiae are heritable aggregates of misfolded proteins, passed to daughter cells following fragmentation by molecular chaperones including the J-protein Sis1, Hsp70 and Hsp104. Overexpression of Hsp104 efficiently cures cell populations of the prion [PSI⁺ ] by an alternative Sis1-dependent mechanism that is currently the subject of significant debate. Here, we broadly investigate the role of J-proteins in this process by determining the impact of amyloid polymorphisms (prion variants) on the ability of well-studied Sis1 constructs to compensate for Sis1 and ask whether any other S. cerevisiae cytosolic J-proteins are also required for this process. Our comprehensive screen, examining all 13 members of the yeast cytosolic/nuclear J-protein complement, uncovered significant variant-dependent genetic evidence for a role of Apj1 (antiprion DnaJ) in this process. For strong, but not weak [PSI⁺ ] variants, depletion of Apj1 inhibits Hsp104-mediated curing. Overexpression of either Apj1 or Sis1 enhances curing, while overexpression of Ydj1 completely blocks it. We also demonstrated that Sis1 was the only J-protein necessary for the propagation of at least two weak [PSI⁺ ] variants and no J-protein alteration, or even combination of alterations, affected the curing of weak [PSI⁺ ] variants, suggesting the possibility of biochemically distinct, variant-specific Hsp104-mediated curing mechanisms.

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