Variant‐specific and reciprocal Hsp40 functions in Hsp104‐mediated prion elimination |
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| Authors: | Michael T. Astor Erina Kamiya Zachary A. Sporn Scott E. Berger Justin K. Hines |
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| Affiliation: | Department of Chemistry, Lafayette College, Easton, PA, USA |
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| Abstract: | 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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