The Yeast [PSI+] Prion: Making Sense of Nonsense

The [PSI +] element was first described by Brian Cox in 1965 (1Cox B.S. Heredity. 1965; 20: 505-521Crossref Scopus (470) Google Scholar) in the course of his studies of a Mendelian nonsense suppressor. The efficiency with which this suppressor could misread UAA stop codons as sense was dependent upon the presence of a non-Mendelian factor, which Cox named [PSI +]. Nearly 30 years of intriguing investigations followed, but the molecular nature of [PSI +] remained unclear (see Refs. 2Cox B.S. Tuite M.F. McLaughlin C.S. Yeast. 1988; 4: 159-178Crossref PubMed Scopus (171) Google Scholar and 3Cox B.S. Hall M.N. Linder P. The Early Days of Yeast Genetics. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1993: 219-239Google Scholar for excellent reviews of this period). Recent reviews (e.g.Refs. 4Cox B. Curr. Biol. 1994; 4: 744-748Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 5Lindquist S. Cell. 1997; 89: 495-498Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 6Kushnirov V.V. Ter-Avanesyan M.D. Cell. 1998; 94: 13-16Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 7Tuite M.F. Lindquist S.L. Trends Genet. 1996; 12: 467-471Abstract Full Text PDF PubMed Scopus (64) Google Scholar, 8Wickner R.B. Masison D.C. Edskes H.K. Yeast. 1995; 11: 1671-1685Crossref PubMed Scopus (140) Google Scholar, 9Wickner R.B. Masison D.C. Curr. Top. Microbiol. Immunol. 1996; 207: 147-160PubMed Google Scholar) incorporate these data with current results in the context of the startling hypothesis (Ref. 10Wickner R.B. Science. 1994; 264: 566-569Crossref PubMed Scopus (1086) Google Scholar and see below) that [PSI +] is a prion. Although the original suppressor mutation acted on by [PSI +] was in a tRNA gene and was specific for UAA codons, [PSI +] was later shown to enhance the efficiency of suppression caused by other nonsense and frameshift tRNA suppressors or by aminoglycoside antibiotics (allosuppression). Eventually [PSI +] was shown to be an “omnipotent” suppressor because it could cause readthrough of certain UAA, UAG, and UGA codons in the absence of other suppressors or drugs (11Liebman S.W. Sherman F. J. Bacteriol. 1979; 139: 1068-1071Crossref PubMed Google Scholar). Similar allosuppressor and omnipotent suppressor phenotypes were also associated with different sup35 andsup45 mutant alleles. However, whereas the sup35and sup45 mutations were recessive and showed the 2:2 segregation pattern expected of Mendelian genes, the [PSI +] factor was dominant and segregated 4:0,i.e. to all meiotic progeny. Consistent with this non-Mendelian segregation, the [PSI +] factor appeared to be located in the cytoplasm because it was transmitted by cytoduction when the cytoplasm of a [PSI +] donor haploid was transferred to a [psi −] recipient haploid without altering the recipient's nucleus (2Cox B.S. Tuite M.F. McLaughlin C.S. Yeast. 1988; 4: 159-178Crossref PubMed Scopus (171) Google Scholar). Thus it was possible that a cytoplasmic nucleic acid encoded [PSI +], although it was shown not to depend upon mitochondrial DNA, 2μ DNA, killer viruses, or 20 S RNA (2Cox B.S. Tuite M.F. McLaughlin C.S. Yeast. 1988; 4: 159-178Crossref PubMed Scopus (171) Google Scholar, 12Tuite M.F. Lund P.M. Futcher A.B. Dobson M.J. Cox B.S. McLaughlin C.S. Plasmid. 1982; 8: 103-111Crossref PubMed Scopus (26) Google Scholar,13Young C.S. Cox B.S. Heredity. 1972; 28: 189-199Crossref PubMed Scopus (23) Google Scholar). The findings that “mutations” of [PSI +] to [psi −] were induced by conventional mutagens with single-hit kinetics and that UV mutagenesis was dependent upon DNA repair genes and was reduced by photoreactivation suggested that [PSI +] was encoded by single-copy DNA (14Tuite M.F. Cox B.S. Genetics. 1980; 95: 611-630PubMed Google Scholar). However, growth in the presence of the mild protein denaturant guanidine hydrochloride or various stress-inducing agents, none of which cause the mutation of nuclear genes, caused the efficient loss of [PSI +]. The kinetics of loss suggested that [PSI +] was encoded by a multicopy element. Another important [PSI] paradox was the observation that although [PSI +] was dominant in vivo, it was recessive in vitro, because mixtures of [PSI +] and [psi−] lysates used in a cell-free translation system did not exhibit the high level of readthrough of nonsense codons characteristic of [PSI +] lysates (15Tuite M.F. Cox B.S. McLaughlin C.S. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 2824-2828Crossref PubMed Scopus (28) Google Scholar). In 1994, Reed Wickner (10Wickner R.B. Science. 1994; 264: 566-569Crossref PubMed Scopus (1086) Google Scholar) presented evidence that [URE3] is a prion form of the Ure2 protein (see accompanying review by Wickner et al. (58Wickner R.B. Edskes H.K. Maddelein M.-L. Taylor K. Moriyama H. J. Biol. Chem. 1999; 274: 555-558Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar)) and at the same time suggested that [PSI +] is a prion form of the Sup35 protein (Sup35p). This revolutionary hypothesis (Table I) explained much of the old [PSI +] data as well as two newer results that directly linked SUP35 to [PSI +] (16Chernoff Y.O. Derkach I.L. Inge-Vechtomov S.G. Curr. Genet. 1993; 24: 268-270Crossref PubMed Scopus (257) Google Scholar, 17Doel S.M. McCready S.J. Nierras C.R. Cox B.S. Genetics. 1994; 137: 659-670Crossref PubMed Google Scholar). The idea was not that Sup35p (or Ure2p) had any functional similarity with the mammalian PrPSc prion but rather that all three had a similar novel mode of inheritance involving the self-propagation of alternate protein conformations.Table IKey evidence supporting the prion hypothesis for [PSI+]Inheritance of [PSI+] is non-MendelianPropagation of [PSI+] requires the presence of theSUP35 gene[PSI+] and mutations inSUP35 have the same phenotypesOverproduction of Sup35p efficiently induces [PSI+][PSI+] can reappear after it is curedPropagation of [PSI+] requires an intermediate level of Hsp104pSup35p forms protease-resistant aggregates in [PSI+] but not [psi−] strainsSup35p forms fibersin vitroSup35pPSI+ efficiently converts Sup35ppsi− to an aggregated protease-resistant form in vitro Open table in a new tab It was proposed (10Wickner R.B. Science. 1994; 264: 566-569Crossref PubMed Scopus (1086) Google Scholar) that in [psi −] cells the conformation of Sup35p is fully functional (Sup35ppsi−) and promotes efficient termination at stop codons. Indeed, we now know that Sup35p is translational release factor eRF3 (see below). In [PSI +] cells some or all of the Sup35p was proposed to take on an alternate conformation (Sup35pPSI+) leading to less efficient termination and thus nonsense suppression. The hypothesis also predicts that Sup35pPSI+ catalyzes the conversion of Sup35ppsi− molecules into Sup35pPSI+ (Fig.1). The in vivo dominance and non-Mendelian nature of [PSI +] and the fact that the impairment of Sup35p either by Mendelian mutations inSUP35 or by the presence of [PSI +] causes similar phenotypes is consistent with this model. The prion hypothesis also explains the paradox (see above) that [PSI +] is recessive in vitro because a mixture of [PSI +] and [psi −] lysates would be expected to contain enough fully functional Sup35ppsi− for efficient termination unless the Sup35ppsi− was converted to Sup35pPSI+ in these in vitro mixtures, which was not the case (18Paushkin S.V. Kushnirov V.V. Smirnov V.N. Ter-Avanesyan M.D. Science. 1997; 277: 381-383Crossref PubMed Scopus (200) Google Scholar). In 1993 the curious finding was reported that a multicopy plasmid carrying SUP35 efficiently induced the de novoappearance of [PSI +] (16Chernoff Y.O. Derkach I.L. Inge-Vechtomov S.G. Curr. Genet. 1993; 24: 268-270Crossref PubMed Scopus (257) Google Scholar). This result was interpreted (10Wickner R.B. Science. 1994; 264: 566-569Crossref PubMed Scopus (1086) Google Scholar) as evidence for the prion model because theSUP35 overexpression increased the probability that a Sup35ppsi− molecule would take on a prion shape by chance. It was also shown that [PSI +] could reappear after curing (16Chernoff Y.O. Derkach I.L. Inge-Vechtomov S.G. Curr. Genet. 1993; 24: 268-270Crossref PubMed Scopus (257) Google Scholar, 19Lund P.M. Cox B.S. Genet. Res. 1981; 37: 173-182Crossref PubMed Scopus (97) Google Scholar), arguing against the possibility that curing was because of the loss of a cytoplasmic nucleic acid with no nuclear master gene. The other crucial result connecting SUP35 with [PSI +] that influenced the prion hypothesis was that a dominant mutation, which caused the loss of [PSI +], PNM2(Psi-No-More) (20Young C.S.H. Cox B.S. Heredity. 1971; 26: 413-522Crossref Scopus (49) Google Scholar), was an allele of SUP35 with a missense mutation that altered the N-terminal region of Sup35p (3Cox B.S. Hall M.N. Linder P. The Early Days of Yeast Genetics. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1993: 219-239Google Scholar, 17Doel S.M. McCready S.J. Nierras C.R. Cox B.S. Genetics. 1994; 137: 659-670Crossref PubMed Google Scholar). At about the same time another paper showed that cells bearing a deletion of the N-terminal coding region of SUP35 were unable to maintain [PSI +] (21Ter-Avanesyan M.D. Dagkesamanskaya A.R. Kushnirov V.V. Smirnov V.N. Genetics. 1994; 137: 671-676Crossref PubMed Google Scholar). These results are analogous to the requirements for the Prn-p and URE2 genes for susceptibility to prion infection and maintenance of [URE3], respectively. The host genes encoding PrP, Ure2p, and Sup35p must be present to provide a continuous supply of protein that can be converted to the prion form (see accompanying reviews by Wickner et al. (58Wickner R.B. Edskes H.K. Maddelein M.-L. Taylor K. Moriyama H. J. Biol. Chem. 1999; 274: 555-558Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) and Weissmann (59Weissmann C. J. Biol. Chem. 1999; 274: 3-6Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar)). Additional experiments testing and exploring the prion hypothesis for [PSI +] then followed at a fast pace. The finding that the chaperone protein Hsp104 is required for the propagation of [PSI +] (22Chernoff Y.O. Lindquist S.L. Ono B. Inge-Vechtomov S.G. Liebman S.W. Science. 1995; 268: 880-884Crossref PubMed Scopus (925) Google Scholar) provided dramatic support for the prion model, because the only known function of Hsp104 is to facilitate the folding of proteins (see below). Also in support of the “protein only” hypothesis, the demonstration that the induction of [PSI +] by overexpression ofSUP35 was because of an excess of Sup35 protein and not an excess of SUP35 DNA or mRNA established that Sup35p is not only necessary, but is also sufficient, to cause [PSI +] (23Derkatch I.L. Chernoff Y.O. Kushnirov V.V. Inge-Vechtomov S.G. Liebman S.W. Genetics. 1996; 144: 1375-1386Crossref PubMed Google Scholar). There is now direct evidence that Sup35p exists in different structural states in [PSI +] and [psi −] cells. Sup35p in lysates of [PSI +] but not [psi −] strains showed increased protease resistance and aggregation (24Paushkin S.V. Kushnirov V.V. Smirnov V.N. Ter-Avanesyan M.D. EMBO J. 1996; 15: 3127-3134Crossref PubMed Scopus (469) Google Scholar, 25Patino M.M. Liu J.J. Glover J.R. Lindquist S. Science. 1996; 273: 622-626Crossref PubMed Scopus (572) Google Scholar), two characteristics of mammalian [PSI +] aggregates were by and were in vivo of Sup35p with protein M.M. Liu J.J. Glover J.R. Lindquist S. Science. 1996; 273: 622-626Crossref PubMed Scopus (572) Google Scholar). Sup35p [PSI +] but not [psi −] strains could the N-terminal of Sup35p (24Paushkin S.V. Kushnirov V.V. Smirnov V.N. Ter-Avanesyan M.D. EMBO J. 1996; 15: 3127-3134Crossref PubMed Scopus (469) Google Scholar). Another important the demonstration that Sup35pPSI+ can efficiently the aggregation of Sup35ppsi− [psi −] lysates (18Paushkin S.V. Kushnirov V.V. Smirnov V.N. Ter-Avanesyan M.D. Science. 1997; 277: 381-383Crossref PubMed Scopus (200) Google Scholar). the only that promotes vitro conversion is that the Sup35pPSI+ it that Sup35pPSI+ molecules either not or are unable to the This finding the model that predicts that conversion to the prion conformation upon Sup35p shown to form in vitro, and the of is by the of of J.R. M.M. Liu J.J. Lindquist S. Cell. 1997; 89: Full Text Full Text PDF PubMed Scopus Google Scholar, P. H. K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). Sup35p are similar to associated with certain because and are in Although have not vivo, these results that an and that the in vitro in conformation the for propagation of [PSI +]. These results can be interpreted in of the the of is not as dependent upon the of Sup35p as by the original model J.R. M.M. Liu J.J. Lindquist S. Cell. 1997; 89: Full Text Full Text PDF PubMed Scopus Google Scholar, A. P. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Sup35p can be into three and The is because of function in translation termination (see below). The region and the region are not M.D. Kushnirov V.V. Dagkesamanskaya A.R. Chernoff Y.O. Inge-Vechtomov S.G. Smirnov V.N. Microbiol. 1993; PubMed Scopus Google Scholar), as strains the or maintain [PSI +] (21Ter-Avanesyan M.D. Dagkesamanskaya A.R. Kushnirov V.V. Smirnov V.N. Genetics. 1994; 137: 671-676Crossref PubMed Google Scholar). The to maintain [PSI +] in is the overexpression of the N-terminal of Sup35p as is to the de of [PSI +] as [PSI aggregates with the protein (23Derkatch I.L. Chernoff Y.O. Kushnirov V.V. Inge-Vechtomov S.G. Liebman S.W. Genetics. 1996; 144: 1375-1386Crossref PubMed Google M.M. Liu J.J. Glover J.R. Lindquist S. Science. 1996; 273: 622-626Crossref PubMed Scopus (572) Google Scholar, S.V. Kushnirov V.V. Cox B.S. Tuite M.F. Ter-Avanesyan M.D. EMBO J. 1998; PubMed Scopus Google Scholar). These data that the [PSI +] prion in Sup35p is to the of the of the in vitro experiments described as of the prion model for [PSI were the Sup35p The region of Sup35p two in [PSI +] mutations that [PSI +] propagation or [PSI suppression are located or to these The first region is in and to and phenotypes A. P. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the presence of bearing mutant to a in aggregation of the mutant and Sup35 whereas reduced the aggregation of the mutant The region of and a that are similar to the in the mammalian prion (see 4Cox B. Curr. Biol. 1994; 4: 744-748Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). in the region was described as a dominant mutation S.M. McCready S.J. Nierras C.R. Cox B.S. Genetics. 1994; 137: 659-670Crossref PubMed Google Scholar). It now that this mutation, only causes [PSI +] loss in some and S. Curr. in and can cause the de induction of [PSI +] when S.V. Kushnirov V.V. Cox B.S. Tuite M.F. Ter-Avanesyan M.D. EMBO J. 1998; PubMed Scopus Google in not [PSI +] it the [PSI +] in an (see below). Although [PSI +] and [psi −] strains have known for some it only that not all [PSI +] strains contain the same [PSI +] (23Derkatch I.L. Chernoff Y.O. Kushnirov V.V. Inge-Vechtomov S.G. Liebman S.W. Genetics. 1996; 144: 1375-1386Crossref PubMed Google Scholar). Indeed, [PSI +] with different and [PSI +] can be in the same when the gene is [PSI +] nonsense mutations and are in of progeny. [PSI +] cause of suppression and are These to be associated with the [PSI +] and are not the result of nuclear Although Sup35p is aggregated in and [PSI +] the level and of aggregation are in [PSI +] S. S. and S. for [PSI +] is dominant [PSI but it unclear is in the presence of or the different [PSI +] forms The different [PSI +] are analogous to the that have of the for the prion hypothesis (see accompanying review by Weissmann (59Weissmann C. J. Biol. Chem. 1999; 274: 3-6Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar)). were caused by a strains could mutations in the nucleic because proteins associated with different strains are at different by it proposed that a PrPSc protein can different of prion aggregates S. B. 1995; PubMed Scopus Google Scholar). The finding in of different [PSI +] overexpression of Sup35p is with the hypothesis and by with the mammalian results that is of Sup35pPSI+ conformation or of [PSI +] Indeed, the Sup35p in vitro have shown to in structural or and these forms are not the same that a structural for [PSI +] J.R. M.M. Liu J.J. Lindquist S. Cell. 1997; 89: Full Text Full Text PDF PubMed Scopus Google Scholar). [PSI +] can also be by to overexpression of allele of [PSI +] are and whereas [PSI +] are These data that Sup35p encoded with different Sup35pPSI+ or The [PSI +] strains in various to only [PSI +] described as a non-Mendelian factor with or mutations S.W. Curr. Genet. 8: PubMed Scopus Google Scholar), is a [PSI +], because it now shown to have a suppressor and to an intermediate level of Hsp104 as well as the Sup35p for maintenance and because [PSI +] induced by Sup35p are with protein and the of protein aggregates are to the prion hypothesis, the finding that are in prion maintenance support for the prion Indeed, an intermediate level of the chaperone Hsp104 shown to be required for the maintenance of [PSI +] (22Chernoff Y.O. Lindquist S.L. Ono B. Inge-Vechtomov S.G. Liebman S.W. Science. 1995; 268: 880-884Crossref PubMed Scopus (925) Google Scholar). [PSI +], whereas overexpression of reduced the [PSI +] at a caused the loss of the [PSI +]. cells of [PSI +] by deletion or overexpression of [PSI +] and when [PSI +] is not overexpression of Hsp104 causes release of Sup35p the (24Paushkin S.V. Kushnirov V.V. Smirnov V.N. Ter-Avanesyan M.D. EMBO J. 1996; 15: 3127-3134Crossref PubMed Scopus (469) Google M.M. Liu J.J. Glover J.R. Lindquist S. 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