The ribosome‐associated Hsp40 chaperone Zuo1 antagonizes prion formation in yeast (752.11)

Abstract

Prions are self‐propagating infectious protein conformations. In mammals prions underlie the transmissible spongiform encephalopathies, a set of invariably fatal neurodegenerative disorders associated with misfolding of the mammalian prion protein, PrP. In recent years increasing numbers of fungal proteins capable of infectiously propagating altered conformations have been discovered. Fungal prions are typically not lethal and debate continues as to whether they may have evolutionarily conserved physiological roles rather than representing disease states. To gain insight into the mechanisms by which cells regulate prion formation, propagation and toxicity, we have examined the role of the ribosome‐associated complex (RAC) chaperones in the formation and toxicity of the [PSI+] prion in yeast. The [PSI+] prion results from a self‐propagating aggregated form of the essential translation termination factor Sup35, and is manifested phenotypically as elevated levels of nonsense suppression. We find that yeast cells lacking the Hsp40 chaperone Zuo1 exhibit higher frequencies of spontaneous and induced [PSI+] formation, consistent with a role for the RAC in chaperoning nascent Sup35 to prevent misfolding of the N‐terminal prion domain as it emerges from the ribosome. Notably, formation of [PSI+] in cells lacking Zuo1 is associated with a reduction in fitness. As both ZUO1 deletion and the [PSI+] prion can independently enhance readthrough of stop codons, toxicity may be due to the elevated levels of nonsense suppression in Δzuo1 [PSI+] strains. Studies are currently underway to understand the mechanisms by which deletion of Zuo1 enhances both the formation and toxicity of the [PSI+] prion.Grant Funding Source: Supported by Research Corporation for Science Advancement