Suicidal [
            <i>PSI</i>
            <sup>+</sup>
            ] is a lethal yeast prion

McGlinchey, Ryan P.; Kryndushkin, Dmitry; Wickner, Reed B.

doi:10.1073/pnas.1102762108

Cited by 177 publications

(174 citation statements)

References 41 publications

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“…The extensive cell death found under the stress conditions may have supplied adenine to the remaining cells, allowing residual growth, and thus the apparent slight elevation of [PSI+] clones recovered may have resulted from underestimating the population from which those clones arose. We find that these stress conditions do not elevate [PSI+] (19). Extensive barriers to transmission of [PSI+] between wild S. cerevisiae have been found, suggesting that this protection from "catching" a prion has been selected in evolution (34).…”

Section: Discussionmentioning

confidence: 78%

“…Our results indicate that this assumption results in a 1,000-fold underestimate of the rate of spread of [PSI+] and a comparable 100-fold underestimate of the degree of detriment it must impart to remain so rare. In addition, the assumption that [PSI+] arises at a frequency of 10 −5 is based on determinations that ignore the greater number of very sick or suicidal [PSI+] that now are known (19) and the likelihood that other lethal forms of the prion exist. It was argued (29) In sexual organisms, the mutation rate appears to be lowered to a level limited by the cost of further fidelity [reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

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Sex, prions, and plasmids in yeast

Kelly

Shewmaker

Kryndushkin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Even deadly prions may be widespread in nature if they spread by infection faster than they kill off their hosts. The yeast prions [PSI+] and [URE3] (amyloids of Sup35p and Ure2p) were not found in 70 wild strains, while [PIN+] (amyloid of Rnq1p) was found in ∼16% of the same population. Yeast prion infection occurs only by mating, balancing the detrimental effects of carrying the prion. We estimated the frequency of outcross mating as about 1% of mitotic doublings from the known detriment of carrying the 2-μm DNA plasmid (∼1%) and its frequency in wild populations (38/70). We also estimated the fraction of total matings that are outcross matings (∼23-46%) from the fraction of heterozygosity at the highly polymorphic RNQ1 locus (∼46% [PIN+] of S. cerevisiae are parallel in-register β-sheet amyloids of Sup35p, Ure2p, and Rnq1p, respectively (7-10); the [Het-s] prion of P. anserina is a β-helical amyloid of the HET-s protein (11). Sup35p is a subunit of the translation termination factor (12, 13), Ure2p is a regulator of nitrogen catabolism (14), and Rnq1p has no known function (15).The mammalian prions are uniformly lethal but nonetheless are found in wild animals. For example, chronic wasting disease of deer and elk is found in ∼10% of wild deer in parts of Wyoming, Colorado, Illinois, and Wisconsin (16). Evidently, infectious spread outpaces the lethal effects on the animals. The [Het-s] prion of P. anserina is involved in heterokaryon incompatibility, a normal function of that species, and, as a result, ∼80% of wild strains with the appropriate chromosomal genotype carry the [Het-s] (20), a result confirmed by others (21) and which we interpreted as meaning that they are substantially detrimental. Nonetheless, others argue that these prions are beneficial, promoting survival by allowing cells to resist stress (22, 23), although the reported effects were not reproducible with the same strains (24). It is reported further that certain stress conditions increase the frequency of[PSI+] when assayed using a synthetic Sup35p with an elevated prion-forming tendency (25). Here we test these conditions for an effect on prion formation by the wild-type Sup35p.Our argument, that the rare occurrence of an infectious agent in nature implies pathologic effects on the host, relies on outcross mating being a fairly frequent event. Yeast prions spread only by mating (there is no extracellular prion species in the replication cycle), and if outcross mating is extremely rare, then yeast prions could be rare even if their effects on the host were neutral. Yeast spores germinate with mating type either a or α, and a and α spores from the same tetrad may mate (intratetrad or brothersister). The mating-type switching system (homothallism) results in the clone from a single germinated spore becoming a mixture of a and α cells which can mate with each other. These two kinds of "selfing" are unlikely to spread any virus, plasmid, or prion, because probably both mating partners will lack the element, or both will have it. Alternat...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Sex, prions, and plasmids in yeast

Kelly

Shewmaker

Kryndushkin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Ure2p normally functions as a soluble regulator of nitrogen catabolism (5,6), and its conversion to the aggregated amyloid prion form produces inappropriate derepression of many genes of nitrogen catabolism, resulting in slightly slowed growth (7). Many [URE3] isolates have a severe toxic effect, producing extremely slowed growth (8). A single protein sequence can assume any of many different heritable/infectious forms with different biological properties and, one infers, different protein conformations.…”

Section: T He Yeast Prion [Ure3] Is a Self-propagating Amyloid Of Ure2pmentioning

confidence: 99%

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

Wickner

Bezsonov

Bateman

2014

Proc. Natl. Acad. Sci. U.S.A.

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[URE3] is an amyloid prion of the Saccharomyces cerevisiae Ure2p, a regulator of nitrogen catabolism. Overproduction of Btn2p, involved in late endosome to Golgi protein transport, or its paralog Cur1p, cures [URE3]. Btn2p, in curing, is colocalized with Ure2p in a single locus, suggesting sequestration of Ure2p amyloid filaments. We find that most [URE3] variants generated in a btn2 cur1 double mutant are cured by restoring normal levels of Btn2p and Cur1p, with both proteins needed for efficient curing. (1-4). Ure2p normally functions as a soluble regulator of nitrogen catabolism (5, 6), and its conversion to the aggregated amyloid prion form produces inappropriate derepression of many genes of nitrogen catabolism, resulting in slightly slowed growth (7). Many [URE3] isolates have a severe toxic effect, producing extremely slowed growth (8). A single protein sequence can assume any of many different heritable/infectious forms with different biological properties and, one infers, different protein conformations. The parallel in-register β-sheet architecture of the [URE3] prion amyloid (9) can explain the templating properties of this prion (10) and the ability of the Ure2p amyloid to act as a gene with multiple alleles (4).[PSI+] is similarly an amyloid prion of Sup35p, a subunit of the translation termination factor [reviewed by Liebman and Chernoff (11)], and [PIN+] is a prion of Rnq1p, a protein of unknown function (12)(13)(14).Eukaryotic cells deal with protein aggregates in several ways, including resolubilization, degradation, sequestration, and combinations of these processes. Several organelles and systems have been recognized to play a role in these processes, including vacuoles (the yeast equivalent of the mammalian lysosomes), the ubiquitin-proteasome systems, the autophagy system, and the various chaperones.In mammalian cells the aggresome is a centrosomal structure to which aggregates are brought in a microtubule-dependent process (15). A yeast site near the spindle pole body (the yeast centrosome) collects huntingtin/polyQ aggregates in a process that depends on microtubule function, suggesting that this is the yeast aggresome (16). Bmh1p, a 14-3-3 protein, was found associated with huntingtin in yeast aggresomes, and bmh1Δ prevented aggresome accumulation of huntingtin (16).Btn2p and Cur1p were found to cure the [URE3] prion when overproduced (17). These proteins are paralogs, members of the Hook family, consistent with their similar effects, but Btn2 localized to a site next to the nucleus, whereas Cur1 was localized largely within the nucleus (17). During the curing process, those [URE3] cells having both Ure2p-GFP aggregates and Btn2-RFP dots show striking colocalization (17-19). Partial colocalization of Btn2-RFP with Sup35NM-GFP in a [PSI+] strain or with the huntingtin-like Q103-GFP were also observed (17), but overexpression of Btn2p or Cur1p did not cure [PSI+]. Doubly deleted btn2Δ cur1Δ strains show an elevated seed number of [URE3] and partial resistance to prion curing by dimethyl sul...

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“…1 In the budding yeast Saccharomyces cerevisiae several different proteins can propagate alternative conformations via a prion-like mechanism and thus serve as epigenetic switches that produce heritable phenotypes. 2 Although it has been suggested that yeast prions represent disease states, [3][4][5][6] the evolution of prion domains in a variety of yeast proteins and the occurrence of prions in wild yeast populations raise the possibility that such a mechanism may also have important biological roles. 7,8 A well-studied example is the [PSI C ] prion, which is a selfpropagating amyloid form of the translation termination factor Sup35.…”

Section: Introductionmentioning

confidence: 99%

The ribosome-associated complex antagonizes prion formation in yeast

Amor

Castanzo

Delany

et al. 2015

Prion

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ABSTRACT. The number of known fungal proteins capable of switching between alternative stable conformations is steadily increasing, suggesting that a prion-like mechanism may be broadly utilized as a means to propagate altered cellular states. To gain insight into the mechanisms by which cells regulate prion formation and toxicity we examined the role of the yeast ribosome-associated complex (RAC) in modulating both the formation of the [PSI C ] prion -an alternative conformer of Sup35 protein -and the toxicity of aggregation-prone polypeptides. The Hsp40 RAC chaperone Zuo1 anchors the RAC to ribosomes and stimulates the ATPase activity of the Hsp70 chaperone Ssb. We found that cells lacking Zuo1 are sensitive to over-expression of some aggregation-prone proteins, including the Sup35 prion domain, suggesting that co-translational protein misfolding increases in Dzuo1 strains. Consistent with this finding, Dzuo1 cells exhibit higher frequencies of spontaneous and induced prion formation. Cells expressing mutant forms of Zuo1 lacking either a C-terminal charged region required for ribosome association, or the J-domain responsible for Ssb ATPase stimulation, exhibit similarly high frequencies of prion formation. Our findings are consistent with a role for the RAC in chaperoning nascent Sup35 to regulate folding of the N-terminal prion domain as it emerges from the ribosome.

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Suicidal [ PSI ⁺ ] is a lethal yeast prion

Cited by 177 publications

References 41 publications

Sex, prions, and plasmids in yeast

Sex, prions, and plasmids in yeast

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

The ribosome-associated complex antagonizes prion formation in yeast

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Suicidal [ PSI + ] is a lethal yeast prion

Cited by 177 publications

References 41 publications

Sex, prions, and plasmids in yeast

Sex, prions, and plasmids in yeast

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

The ribosome-associated complex antagonizes prion formation in yeast

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Suicidal [ PSI ⁺ ] is a lethal yeast prion