The word 'prion'means 'infectious protein', a protein which can transmit a disease or trait without the necessity for an accompanying nucleic acid. The prion concept has its origins in studies of the mammalian transmissible spongiform encephalopathies, a group of uniformly fatal diseases whose underlying cause appears to be the formation of amyloid composed of the PrP protein. In 1994, we discovered two prions of the yeast Saccharomyces cerevisiae, called URE3 and PSI, based on a self-propagating inactivation of the Ure2 and Sup35 proteins, respectively (1). Ure2p is a regulator of nitrogen catabolism and URE3 strains show a derepression of the genes normally repressed by this protein. Sup35p is a subunit of the translation termination factor, and PSI+ strains show elevated readthrough of translation termination codons, a phenotype similar to that of a sup35 mutant. Another yeast prion, PIN+ and a prion of the filamentous fungus Podospora anserina have since been described (2,3). Each of these yeast and fungal prions are based on self-propagating amyloid formation by a chromosomally encoded protein. Most amyloid formation in humans, and certainly the transmissible spongiform encephalopathies are disease-associated phenomena. However, the yeast prions URE3, PSI+ and PIN+ and the fungal prion Het-s do not immediately kill off their hosts and are compatible with survival. We proposed (4) that the Het-s prion was an advantage to its host Podospora because it is necessary for heterokaryon incompatibility, a phenomenon like transplant rejection in mammals with the het-s locus playing the role of HLA. It was also proposed that PSI+ protects cells from stress (5), and another group claimed that PSI+ helps yeast evolve, based on a large series of tests comparing growth of PSI+ and psi- strains (6). We designed a simple test of this idea (7): infectious viruses and plasmids (and mammalian prions such as Chronic Wasting disease of elk and deer or scrapie of sheep) are easily found in natural isolates even if they are a detriment to their hosts. This is simply because their infectivity spreads them in spite of hurting or perhaps killing each host they infect. Certainly an advantageous infectious entity would be widely found in the wild. The mitochondria, which started as a bacterial infection, is a good example of an infectious advantageous entity. Thus, an infectious element that is not found widely in natural isolates must be a disadvantage to its host. We surveyed 70 wild strains, and found that none of them carried URE3 or PSI+, although all of the other known yeast infectious elements (DNA plasmids and RNA viruses known to be a mild detriment to the host) were found, some in over half the strains (7). This shows that on the net, URE3 and PSI+ are a rather severe detriment to their host. The PIN+ prion was found at rates comparable to the mildly detrimental nucleic acid replicons, suggesting that it is not so severe a problem for yeast. If URE3 is a disease, why is the Ure2p prion domain maintained in evolution? We previously showed that the C-terminal part of Ure2p, when overexpressed a few fold from a plasmid, is capable of full function in nitrogen catabolite repression (8). However, more careful assessment of this issue showed that when expressed from the normal chromosomal site at normal levels, Ure2p is unstable if lacking its prion domain (9). It also fails to interact properly with some other proteins involved in control of nitrogen catabolism (9). This partially defective phenotype of lacking the 'prion domain'is sufficient to explain why this region is retained in evolution. Similarly, the prion domain of Sup35p is required for normal turnover of all mRNAs (10). A broken leg does not explain the retention of legs in evolution, and the prion change is an analogous unfortunate molecular accident. Recently, we have described a new prion, called MCA, identified by a general unbiased screen for prion domains (11). This prion is a self-propagating aggregated form of Mca1p, a yeast homolog of mammalian metacaspases. Like the prion domain of Ure2p, the prion domain of Mca1p is very rich in asparagine and glutamine residues (11) and can serve to stabilize Ure2p (9). It is argued that the conservation of prion-forming ability in evolution implies that yeast prions are functional for their hosts. However, we find that the Ure2p of S. castellii is unable to be a prion (12), and Tuite's group has found that 1/4 of wild S. cerevisiae Sup35 alleles have a large deletion in their prion domains making them unable to be a prion (13). Thus, prion forming ability is not conserved. 1. Wickner, R. B. URE3 as an altered URE2 protein: evidence for a prion analog in S. cerevisiae. Science 264, 566 - 569 (1994). 2. Coustou, V., Deleu, C., Saupe, S., and Begueret, J. (1997). The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc. Natl. Acad. Sci. U. S. A. 94, 9773 - 9778. 3. Derkatch, I.L., Bradley, M.E., Hong, J.Y., and Liebman, S.W. (2001). Prions affect the appearance of other prions: the story of PIN. Cell 106, 171 - 182. 4. Wickner, R.B. (1997). A new prion controls fungal cell fusion incompatibility. Proc. Natl. Acad. Sci. U. S. A. 94, 10012 - 10014. 5. Eaglestone, S.S., Cox, B.S., and Tuite, M.F. (1999). Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism. EMBO J. 18, 1974 - 1981. 6. True, H.L., and Lindquist, S.L. (2000). A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477-483. 7. Nakayashiki, T., Kurtzman, C.P., Edskes, H.K., and Wickner, R.B. (2005). Yeast prions URE3 and PSI+ are diseases. Proc Natl Acad Sci U S A 102, 10575-10580. 8. Masison, D.C., and Wickner, R.B. (1995). Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells. Science 270, 93 - 95. 9. Shewmaker, F., Mull, L., Nakayashiki, T., Masison, D.C., and Wickner, R.B. (2007). Ure2p function is enhanced by its prion domain in Saccharomyces cerevisiae. Genetcs 176, 1557 - 1565. 10. Hosoda N, Kobayashii T, Uchida N, Funakoshi Y, Kikuchi Y, Hoshino S &Katada T (2003) Translation termination factor eRF3 mediates mRNA decay through the regulation of deadenylation. J. Biol. Chem. 278: 38287 - 38291. 11. Nemecek J, Nakayashiki T &Wickner RB (2008) A prion of yeast metacaspase homolog (Mca1p) detected by a genetic screen. Proc. Natl. Acad. Sci. USA 106: 1892 - 1896. 12. Edskes HK, McCann LM, Hebert AM &Wickner RB (2009) Prion variants and species barriers among Saccharomyces Ure2 proteins. Genetics 181: 1159 - 1167. 13. Resende CG, Outeiro TF, Sands L, Lindquist S &Tuite MF (2003) Prion protein gene polymorphisms in Saccharomyces cerevisiae. Mol. Microbiol. 49: 1005 - 1017.
| Wickner, Reed B; Edskes, Herman K; Son, Moonil et al. (2018) Yeast Prions Compared to Functional Prions and Amyloids. J Mol Biol : |
| Wickner, Reed B; Edskes, Herman K; Bezsonov, Evgeny E et al. (2018) Prion propagation and inositol polyphosphates. Curr Genet 64:571-574 |
| Wickner, Reed B; Bezsonov, Evgeny E; Son, Moonil et al. (2018) Anti-Prion Systems in Yeast and Inositol Polyphosphates. Biochemistry 57:1285-1292 |
| Wickner, Reed B; Kryndushkin, Dmitry; Shewmaker, Frank et al. (2018) Study of Amyloids Using Yeast. Methods Mol Biol 1779:313-339 |
| Son, Moonil; Wickner, Reed B (2018) Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants. Proc Natl Acad Sci U S A 115:E1184-E1193 |
| Edskes, Herman K; Mukhamedova, Maryam; Edskes, Bouke K et al. (2018) Hermes Transposon Mutagenesis Shows [URE3] Prion Pathology Prevented by a Ubiquitin-Targeting Protein: Evidence for Carbon/Nitrogen Assimilation Cross Talk and a Second Function for Ure2p in Saccharomyces cerevisiae. Genetics 209:789-800 |
| Edskes, Herman K; Kryndushkin, Dmitry; Shewmaker, Frank et al. (2017) Prion Transfection of Yeast. Cold Spring Harb Protoc 2017:pdb.prot089037 |
| Wickner, Reed B; Kelly, Amy C; Bezsonov, Evgeny E et al. (2017) [PSI+] prion propagation is controlled by inositol polyphosphates. Proc Natl Acad Sci U S A 114:E8402-E8410 |
| Gorkovskiy, Anton; Reidy, Michael; Masison, Daniel C et al. (2017) Hsp104 disaggregase at normal levels cures many [PSI(+)] prion variants in a process promoted by Sti1p, Hsp90, and Sis1p. Proc Natl Acad Sci U S A 114:E4193-E4202 |
| Wickner, Reed B; Edskes, Herman K; Kryndushkin, Dmitry et al. (2017) Genetic Methods for Studying Yeast Prions. Cold Spring Harb Protoc 2017:pdb.prot089029 |
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