RESEARCH ARTICLE The 26S Proteasome Degrades the Soluble but Not the Fibrillar Form of the Yeast Prion

Yeast prions are self-perpetuating protein aggregates that cause heritable and transmissi-ble phenotypic traits. Among these, [PSI+] and [URE3] stand out as the most studied yeast prions, and result from the self-assembly of the translation terminator Sup35p and the nitro-gen catabolism regulator Ure2p, respectively, into insoluble fibrillar aggregates. Protein quality control systems are well known to govern the formation, propagation and transmis-sion of these prions. However, little is known about the implication of the cellular proteolytic machineries in their turnover. We previously showed that the 26S proteasome degrades both the soluble and fibrillar forms of Sup35p and affects [PSI+] propagation. Here, we show that soluble native Ure2p is degraded by the proteasome in an ubiquitin-independent man-ner. Proteasomal degradation of Ure2p yields amyloidogenic N-terminal peptides and a C-terminal resistant fragment. In contrast to Sup35p, fibrillar Ure2p resists proteasomal degra-dation. Thus, structural variability within prions may dictate their ability to be degraded by the cellular proteolytic systems