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); 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. A broken leg does not explain the retention of legs in evolution, and the prion change is an analogous unfortunate molecular accident.? The prion domain of Ure2p is very rich in asparagine and glutamine residues, and many other proteins have such Q/N-rich domains, most of which do not show prion-like properties. We showed that one of these Q/N rich domains, which otherwise bears no similarity to the Ure2p prion domain, can serve to stabilize Ure2p (9).? 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.
| Edskes, Herman K; McCann, Lindsay M; Hebert, Andrea M et al. (2009) Prion variants and species barriers among Saccharomyces Ure2 proteins. Genetics 181:1159-67 |
| Krammer, Carmen; Kryndushkin, Dmitry; Suhre, Michael H et al. (2009) The yeast Sup35NM domain propagates as a prion in mammalian cells. Proc Natl Acad Sci U S A 106:462-7 |
| Nemecek, Julie; Nakayashiki, Toru; Wickner, Reed B (2009) A prion of yeast metacaspase homolog (Mca1p) detected by a genetic screen. Proc Natl Acad Sci U S A 106:1892-6 |
| Wickner, Reed B; Edskes, Herman K; Shewmaker, Frank et al. (2007) Prions of fungi: inherited structures and biological roles. Nat Rev Microbiol 5:611-8 |
| Shewmaker, Frank; Mull, Lori; Nakayashiki, Toru et al. (2007) Ure2p function is enhanced by its prion domain in Saccharomyces cerevisiae. Genetics 176:1557-65 |
| Shewmaker, Frank; Wickner, Reed B (2006) Ageing in yeast does not enhance prion generation. Yeast 23:1123-8 |
