The Copper Transport-associated Protein Ctr4 Can Form Prion-like Epigenetic Determinants in

Prions are protein-based infectious entities associated with fatal brain diseases in animals, but also modify a range of host-cell phenotypes in the budding yeast, . Many questions remain about the evolution and biology of prions. Although several functionally distinct prion-forming proteins exist in , [HET-s] of is the only other known fungal prion. Here we investigated prion-like, protein-based epigenetic transmission in the fission yeast . We show that cells can support the formation and maintenance of the prion form of the Sup35 translation factor [], and that the formation and propagation of these Sup35 aggregates is inhibited by guanidine hydrochloride, indicating commonalities in prion propagation machineries in these evolutionary diverged yeasts. A proteome-wide screen identified the Ctr4 copper transporter subunit as a putative prion with a predicted prion-like domain. Overexpression of the gene resulted in large Ctr4 protein aggregates that were both detergent and proteinase-K resistant. Cells carrying such [] aggregates showed increased sensitivity to oxidative stress, and this phenotype could be transmitted to aggregate-free [] cells by transformation with [] cell extracts. Moreover, this [] phenotype was inherited in a non-Mendelian manner following mating with naïve [] cells, but intriguingly the [] phenotype was not eliminated by guanidine-hydrochloride treatment. Thus, Ctr4 exhibits multiple features diagnostic of other fungal prions and is the first example of a prion in fission yeast. These findings suggest that transmissible protein-based determinants of traits may be more widespread among fungi.