Abstract
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, Saccharomyces cerevisiae. Many questions remain about the evolution and biology of prions. Although several functionally distinct prion-forming proteins exist in S. cerevisiae, [HET-s] of Podospora anserina is the only other known fungal prion. Here we investigated prion-like, protein-based epigenetic transmission in the fission yeast Schizosaccharomyces pombe. We show that S. pombe cells can support the formation and maintenance of the prion form of the S. cerevisiae Sup35 translation factor [PSI+], 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 ctr4 gene resulted in large Ctr4 protein aggregates that were both detergent and proteinase-K resistant. Cells carrying such [CTR+] aggregates showed increased sensitivity to oxidative stress, and this phenotype could be transmitted to aggregate-free [ctr-] cells by transformation with [CTR+] cell extracts. Moreover, this [CTR+] phenotype was inherited in a non-Mendelian manner following mating with naïve [ctr-] cells, but intriguingly the [CTR+] 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.
Highlights
Prions were first identified as infectious amyloid forms of the mammalian protein PrP that can be transmitted from organism to organism [1]
Fission yeast supports formation of the budding yeast [PSI+] prion To test whether S. pombe cells can propagate the prion form of a protein, we first tested whether overexpression of the NM region of the S. cerevisiae Sup35 protein (ScSup35) fused to GFP resulted in the generation of heritable protein aggregates
A prion-like state has been reported in fission yeast that allows cells to survive in the absence of the essential chaperone calnexin, the responsible protein(s) that determine this phenotype remain to be identified [65]
Summary
Prions were first identified as infectious amyloid forms of the mammalian protein PrP that can be transmitted from organism to organism [1]. They were subsequently shown to exist in two fungal species, Saccharomyces cerevisiae and Podospora anserina [2] and more recently in plants [3]. [4, 5] In each case, these fatal neurodegenerative diseases are associated with refolding of the soluble form of PrP (PrPc) into a distinct conformational state designated PrPSc. The infectious PrPSc conformer can catalyse the refolding of other PrPc molecules into the PrPSc conformation, which over time leads to amyloid fibrils that form highly ordered aggregates with a characteristic cross βsheet conformation [6]. These amyloid forms are characteristic of the protein aggregates deposited in the brains of Alzheimer’s, Parkinson’s, and Huntington’s Dis-
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