Prion Variants and Species Barriers Among Saccharomyces Ure2 Proteins

Edskes, Herman K.; McCann, Lindsay M.; Hebert, Andrea; Wickner, Reed B.

doi:10.1534/genetics.108.099929

Cited by 63 publications

(88 citation statements)

References 66 publications

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“…We generated and isolated a large series of [URE3] variants in a btn2Δ cur1Δ strain and restored normal levels of both Btn2p (41)(42)(43), the [URE3-bcs] variants expand the range of known possibilities of yeast prion characteristics. The [URE3-bcs] variants that we describe here would not be detected in a wild-type host, because they are rapidly eliminated by the combined action of Btn2p and Cur1p.…”

Section: Discussionmentioning

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.

120

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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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Section: Discussionmentioning

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.

120

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“…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). The notion that prion-forming ability is generally conserved (46) is not true for Ure2p, as the Saccharomyces castellii, Kluyveromyces lactis, and Candida glabrata Ure2ps cannot become [URE3] even though they are closely related to that of S. cerevisiae Ure2p, whereas the more distantly related Candida albicans Ure2p can form a prion (33,49,50). Prion-forming ability appears to be sporadic rather than conserved.…”

Section: Discussionmentioning

confidence: 99%

“…30), later recognized as a requirement for homozygosity at PrP residue 129 for Creutzfeldt-Jakob disease (31), and recently reported in a barrier to the transmission of [PSI+] and of [URE3] between Saccharomyces species (32,33). Even within S. cerevisiae, there are several groups of polymorphs of Sup35p between which prion transmission is inefficient; we suggest the existence of these polymorphs was selected to protect yeast from the detrimental effects of [PSI+] (34), just as polymorphisms of human PrP are believed to have been selected to protect against kuru-like epidemics of prion disease (31).…”

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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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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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“…Because of the difficulties of Candida genetics, we chose to examine the prion-forming abilities of C. albicans and C. glabrata Ure2p in S. cerevisiae, an approach often used by others as well (Chernoff et al 2000;Kushnirov et al 2000;Santoso et al 2000;Nakayashiki et al 2001). However, while the Ure2p of S. paradoxus forms a prion in S. cerevisiae (Edskes and Wickner 2002;Edskes et al 2009), it was found to not form [URE3] in S. paradoxus itself (Talarek et al 2005), casting doubt on this approach.…”

Section: Methodsmentioning

confidence: 99%

“…While it may be reassuring that S. cerevisiae turns out to be a good test bed for prion formation in this case, there are numerous chromosomal genes affecting prion generation and propagation, so that this assumption may not always prove to be valid in the many studies which have used this approach. The Ure2p of S. castellii is unable to form a prion in S. cerevisiae (Edskes et al 2009), but it has not yet been tested in S. castellii itself. Engineering other organisms to detect prions is a daunting task.…”

Section: Nomenclaturementioning

confidence: 99%

Prion-Forming Ability of Ure2 of Yeasts Is Not Evolutionarily Conserved

et al. 2011

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ABSTRACT[URE3] is a prion (infectious protein) of the Saccharomyces cerevisiae Ure2p, a regulator of nitrogen catabolism. We show that wild S. paradoxus can be infected with a [URE3] prion, supporting the use of S. cerevisiae as a prion test bed. We find that the Ure2p of Candida albicans and C. glabrata also regulate nitrogen catabolism. Conservation of amino acid sequence within the prion domain of Ure2p has been proposed as evidence that the [URE3] prion helps its host. We show that the C. albicans Ure2p, which does not conserve this sequence, can nonetheless form a [URE3] prion in S. cerevisiae, but the C. glabrata Ure2p, which does have the conserved sequence, cannot form [URE3] as judged by its performance in S. cerevisiae. These results suggest that the sequence is not conserved to preserve prion forming ability.

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Prion Variants and Species Barriers Among Saccharomyces Ure2 Proteins

Cited by 63 publications

References 66 publications

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

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

Sex, prions, and plasmids in yeast

Prion-Forming Ability of Ure2 of Yeasts Is Not Evolutionarily Conserved

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