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

Summary Yeast self‐perpetuating protein aggregates (prions) provide a convenient model for studying various components of the cellular protein quality control system. Molecular chaperones and chaperone‐sorting factors, such as yeast Cur1 protein, play key role in proteostasis via tight control of partitioning and recycling of misfolded proteins. In this study, we show that, despite the previously described ability of Cur1 to antagonize the yeast prion [URE3], it enhances propagation and phenotypic manifestation of another prion, [PSI+]. We demonstrate that both curing of [URE3] and enhancement of [PSI+] in the presence of excess Cur1 are counteracted by the cochaperone Hsp40‐Sis1 in a dosage‐dependent manner, and show that the effect of Cur1 on prions parallels effects of the attachment of nuclear localization signal to Sis1, indicating that Cur1 acts on prions via its previously reported ability to relocalize Sis1 from the cytoplasm to nucleus. This shows that the direction in which Cur1 influences a prion depends on how this specific prion responds to relocalization of Sis1. Yeast self‐perpetuating protein aggregates (prions) propagate via tight interaction with molecular chaperones and protein sorting factors. Here we show that the yeast chaperone sorting factor Cur1 enhances [PSI+], but cures [URE3] prion. We also demonstrate that Cur1 influences prion propagation via relocalization of Sis1 cochaperone into the nucleus. Our findings emphasize the importance of spatiotemporal chaperone balance for prion propagation and protein quality control.