Functionally redundant isoforms of a yeast Hsp70 chaperone subfamily have different antiprion effects

Why eukaryotes encode multiple Hsp70 isoforms is unclear. Saccharomyces cerevisiae Ssa1p and Ssa2p are constitutive 98% identical Hsp70's. Stress-inducible Sssa3p and Ssa4p are 80% identical to Ssal/2p. We show Ssa1p-4p have distinct functions affecting [PSI+] and [URE3] prions. When expressed as the only SSa, Ssa1p antagonized [URE3] and Ssa2p antagonized [PSI+]. Ssa3p and Ssa1p influenced [URE3] and [PSI+] Somewhat differently but overall their effects paralleled those of Ssa1p and Ssa2p, respectively. Additionally, Ssa3p suppressed a prion-inhibitory effect of elevated temperature. Our previously described Ssa1-21p mutant weakens [PSI+] in SSA1-21 SSA2 cells and abolishes it in SSA1-21 ssa2 Delta cells. To test if the same mutation affected other prions or altered Ssa2p similarly, we compared effects of a constructed Ssa2-21p mutant and Ssa1-21p on both prions. Surprisingly, [URE3] was unaffected in SSA1-21 SSA2 cells and could propagate in SSA1-21 ssa2 Delta cells. Ssa2-21p impaired [URE3] considerably and weakened [PSI+] strongly but in a manner distinct from Ssa1-21p, highlighting functional differences between these nearly identical Hsp70's. our data uncover exquisite functional differences among isoforms of a highly homologous cytosolic Hsp70 subfamily and point to a possibility that variations in Hsp70 function that might improve fitness under optimal conditions are also important during stress.