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Anti-prion systems in yeast

  • Reed B. Wickner
    Correspondence
    To whom correspondence should be addressed: 8 Center Dr. MSC0830, Bldg. 8, Rm. 225, National Institutes of Health, Bethesda, MD 20892-0830. Tel.: 301-496-3452
    Affiliations
    Laboratory of Biochemistry and Genetics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0830
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Open AccessPublished:February 01, 2019DOI:https://doi.org/10.1074/jbc.TM118.004168
      Yeast prions have become important models for the study of the basic mechanisms underlying human amyloid diseases. Yeast prions are pathogenic (unlike the [Het-s] prion of Podospora anserina), and most are amyloid-based with the same in-register parallel β-sheet architecture as most of the disease-causing human amyloids studied. Normal yeast cells eliminate the large majority of prion variants arising, and several anti-prion/anti-amyloid systems that eliminate them have been identified. It is likely that mammalian cells also have anti-amyloid systems, which may be useful in the same way humoral, cellular, and innate immune systems are used to treat or prevent bacterial and viral infections.

      Herb Tabor, my mentor

      I began my scientific career after completing my medical internship when I became a postdoc with Herb and Celia Tabor in 1967 at the National Institutes of Health. I was fortunate to be working with someone who was such an exceptional model scientist. After 3 years as a postdoc with Jerry Hurwitz in New York, I returned to Herb’s department in an independent position. Herb had built a department of diverse interests that was unified by daily literature and weekly work seminars, both featuring intense discussion and critique. It was an excellent environment for learning and developing one’s own program. Although I became the Lab Chief (NIH’s equivalent of the Department Chair) in 1996, my relationship with Herb has remained essentially unchanged for over 50 years (it took me ∼25 of those years before I switched from “Dr. Tabor” to “Herb”). Herb Tabor is totally devoted to science, has always done experiments himself, is far more concerned about getting the right answer to a problem than in making a splash, and is the least vain of any scientist I have ever met. His total honesty, sincerity, and scientific focus have been a model I have attempted to emulate (though largely without success). His devotion to science did not mean neglect of his family, but rather a total involvement of his family in science. Celia White Tabor worked together with Herb for many years, and all of his wonderful children have had science careers. A large part of Herb’s life has been science in the lab, but an equal or maybe even larger part has been scientific publishing. His technologically forward-looking approach and his broadening the scope and enlarging the size of the JBC had an enormous impact.
      Among the lessons I have learned from Herb are:
      • Any scientific area has the potential to be interesting, if studied with enough depth and skill.
      • “Depth is better than width.”
      • The word “critical” was used in a positive sense to describe someone who could thoughtfully, fairly, and accurately evaluate a piece of work.
      • “Kinetics are meaningless.”
      • “Some scientists may not want to be acknowledged because they do not think much of your work.”
      • “I’ve told you all I know, maybe more.”
      Although my own work has taken a largely genetic direction, the lessons I learned from Herb are not specific to any area of science, and I know I have benefited greatly from his constant example.
      The word “prion,” meaning “infectious protein,” without any nucleic acid being required for the transmission of the infection, originated in studies of the transmissible spongiform encephalopathies of mammals (
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      ). However, the proof of the existence of a prion had to await the discovery that the nonchromosomal genetic elements, [URE3] and [PSI+] of Saccharomyces cerevisiae, are based on altered infectious forms of Ure2p and Sup35p, respectively (
      • Wickner R.B.
      [URE3] as an altered URE2 protein: evidence for a prion analog in S. cerevisiae.
      ). Both the mammalian transmissible spongiform encephalopathies and the yeast prions are self-propagating amyloids. Amyloid is a linear polymer of a particular protein, a sort of one-dimensional crystal in which the predominant structure is β-sheet, with the β-strands perpendicular to the long axis of the filaments. Of late, evidence has been found for prion-like behavior, or even frank infection, for such classical amyloidoses as amyloidosis A (
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      The kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy.
      ,
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      Historical and current concepts of fibrillogenesis and in vivo amyloidogenesis: implications of amyloid tissue targeting.
      ), Alzheimer’s disease (
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      Self-propagation of pathogenic protein aggregates in neurodegenerative diseases.
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      Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue.
      ), multiple system atrophy (
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      Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.
      ), amyotrophic lateral sclerosis (
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      • O'Neal V.M.
      • Diamond J.H.
      • Borchelt D.R.
      Prion-like propagation of mutant SOD1 misfolding and motor neuron disease.
      ), and type 2 diabetes (
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      Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism.
      ). This developing unification of the human amyloidoses around the prion model enhances the importance of an in-depth study of the prions of S. cerevisiae, with their facile genetic manipulability.

      Yeast prions

      Two long-known nonchromosomal genetic elements of yeast, [URE3] (
      • Lacroute F.
      Non-mendelian mutation allowing ureidosuccinic acid uptake in yeast.
      ) and [PSI+] (
      • Cox B.S.
      PSI, a cytoplasmic suppressor of super-suppressor in yeast.
      ), were identified as prions of Ure2p and Sup35p based on their outré genetic properties (
      • Wickner R.B.
      [URE3] as an altered URE2 protein: evidence for a prion analog in S. cerevisiae.
      ). Ure2p, a repressor of genes encoding transporters and assimilation enzymes for poor nitrogen sources, is active when a good nitrogen source is available (
      • Cooper T.G.
      Transmitting the signal of excess nitrogen in Saccharomyces cerevisiae from the Tor proteins to th GATA factors: connecting the dots.
      ), but in [URE3] strains, Ure2p is largely trapped in infectious amyloid filaments (
      • Masison D.C.
      • Wickner R.B.
      Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells.
      • Edskes H.K.
      • Gray V.T.
      • Wickner R.B.
      The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments.
      ,
      • Taylor K.L.
      • Cheng N.
      • Williams R.W.
      • Steven A.C.
      • Wickner R.B.
      Prion domain initiation of amyloid formation in vitro from native Ure2p.
      • Brachmann A.
      • Baxa U.
      • Wickner R.B.
      Prion generation in vitro: amyloid of Ure2p is infectious.
      ). The aggregated form is evidently largely inactive as [URE3] cells have a phenotype similar to ure2Δ cells, the inappropriate derepression of the controlled genes despite the presence of a good nitrogen source. Sup35p is a subunit (with Sup45) of the translational termination factor (
      • Zhouravleva G.
      • Frolova L.
      • Le Goff X.
      • Le Guellec R.
      • Inge-Vechtomov S.
      • Kisselev L.
      • Philippe M.
      Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3.
      ,
      • Stansfield I.
      • Jones K.M.
      • Kushnirov V.V.
      • Dagkesamanskaya A.R.
      • Poznyakovski A.I.
      • Paushkin S.V.
      • Nierras C.R.
      • Cox B.S.
      • Ter-Avanesyan M.D.
      • Tuite M.F.
      The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae.
      ). In [PSI+] cells, Sup35p is in infectious amyloid aggregates (
      • Paushkin S.V.
      • Kushnirov V.V.
      • Smirnov V.N.
      • Ter-Avanesyan M.D.
      Propagation of the yeast prion-like [psi+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor.
      • Paushkin S.V.
      • Kushnirov V.V.
      • Smirnov V.N.
      • Ter-Avanesyan M.D.
      In vitro propagation of the prion-like state of yeast Sup35 protein.
      ,
      • Patino M.M.
      • Liu J.-J.
      • Glover J.R.
      • Lindquist S.
      Support for the prion hypothesis for inheritance of a phenotypic trait in yeast.
      ,
      • King C.-Y.
      • Tittmann P.
      • Gross H.
      • Gebert R.
      • Aebi M.
      • Wüthrich K.
      Prion-inducing domain 2–114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments.
      ,
      • Glover J.R.
      • Kowal A.S.
      • Schirmer E.C.
      • Patino M.M.
      • Liu J.-J.
      • Lindquist S.
      Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae.
      ,
      • King C.-Y.
      • Diaz-Avalos R.
      Protein-only transmission of three yeast prion strains.
      • Tanaka M.
      • Chien P.
      • Naber N.
      • Cooke R.
      • Weissman J.S.
      Conformational variations in an infectious protein determine prion strain differences.
      ), and increased readthrough of stop codons ensues.
      A wide array of other prions has now been found in S. cerevisiae and one particularly revealing prion in the filamentous fungus Podospora anserina (
      • Coustou V.
      • Deleu C.
      • Saupe S.
      • Begueret J.
      The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog.
      ). [PIN+] is an amyloid-based prion of Rnq1p, a protein of unknown function (
      • Derkatch I.L.
      • Bradley M.E.
      • Zhou P.
      • Chernoff Y.O.
      • Liebman S.W.
      Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae.
      ,
      • Sondheimer N.
      • Lindquist S.
      Rnq1: an epigenetic modifier of protein function in yeast.
      • Derkatch I.L.
      • Bradley M.E.
      • Hong J.Y.
      • Liebman S.W.
      Prions affect the appearance of other prions: the story of [PIN].
      ). [PIN+] is manifest only (so far) by its facilitation of the (nonetheless rare) generation of other prions, originally [PSI+] (
      • Derkatch I.L.
      • Bradley M.E.
      • Zhou P.
      • Chernoff Y.O.
      • Liebman S.W.
      Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae.
      ) and later [URE3] (
      • Bradley M.E.
      • Edskes H.K.
      • Hong J.Y.
      • Wickner R.B.
      • Liebman S.W.
      Interactions among prions and prion “strains” in yeast.
      ) and [SWI+] (
      • Du Z.
      • Goncharoff D.K.
      • Cheng X.
      • Li L.
      Analysis of [SWI+] formation and propagation events.
      ). Extensive evidence indicates that this stimulation of prion formation occurs by an inefficient form of the same seeding process that is involved in propagation of all of the amyloid-based yeast prions (
      • Liebman S.W.
      • Chernoff Y.O.
      Prions in yeast.
      ). There is clinical and experimental evidence that similar cross-seeding is an important feature of human amyloidosis (
      • Westermark G.T.
      • Fändrich M.
      • Lundmark K.
      • Westermark P.
      Non-cerebral amyloidoses: aspects on seeding, cross-seeding and transmission.
      ,
      • Moreno-Gonzalez I.
      • Edwards Iii G.
      • Salvadores N.
      • Shahnawaz M.
      • Diaz-Espinoza R.
      • Soto C.
      Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeing of protein misfolding.
      ). Because nearly all known pathogenic amyloids have a similar architecture (see below), it is likely that this potentiation of formation of one prion/amyloid by another is a general phenomenon.
      Prion variants are a feature of all pathogenic prions, whether of animals or yeast (
      • Collinge J.
      • Clarke A.R.
      A general model of prion strains and their pathogenicity.
      ). A single prion protein with a single sequence can be the basis of a wide array of prion variants (or prion strains), with distinct biological properties and different amyloid conformations (
      • Tanaka M.
      • Chien P.
      • Naber N.
      • Cooke R.
      • Weissman J.S.
      Conformational variations in an infectious protein determine prion strain differences.
      ,
      • Bessen R.A.
      • Marsh R.F.
      Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy.
      ). Each variant is relatively stably propagated, implying that there must be a mechanism by which the amyloid filaments act as a template to force monomers joining the end of the filaments to assume the same conformation as molecules already in the filament. In yeast, prion variants may differ in the intensity of their phenotype (strong versus weak), stability of propagation, ability to propagate in the face of overproduction or deficiency of various chaperones or other cell components, ability to cross interspecies or intraspecies barriers, and other properties. Using a nonselective system, it was shown that the [PSI+] prion exists as a “cloud” of prion variants that segregate from each other as cells grow and mutate at some frequency (
      • Bateman D.A.
      • Wickner R.B.
      The [PSI+] prion exists as a dynamic cloud of variants.
      ), thus establishing the “prion cloud” model (
      • Collinge J.
      • Clarke A.R.
      A general model of prion strains and their pathogenicity.
      ,
      • Tanaka M.
      • Chien P.
      • Yonekura K.
      • Weissman J.S.
      Mechanism of cross-species prion transmission: an infectious conformation compatible with two highly divergent yeast prion proteins.
      ).
      Prion domains are the part of the protein that actually forms the amyloid and is roughly the same as the part needed to transmit the prion (
      • Masison D.C.
      • Wickner R.B.
      Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells.
      ,
      • Taylor K.L.
      • Cheng N.
      • Williams R.W.
      • Steven A.C.
      • Wickner R.B.
      Prion domain initiation of amyloid formation in vitro from native Ure2p.
      ,
      • King C.-Y.
      • Tittmann P.
      • Gross H.
      • Gebert R.
      • Aebi M.
      • Wüthrich K.
      Prion-inducing domain 2–114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments.
      ,
      • Ter-Avanesyan M.D.
      • Dagkesamanskaya A.R.
      • Kushnirov V.V.
      • Smirnov V.N.
      The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae.
      ). Both the extent of amyloid structure and the region needed to faithfully propagate the prion vary with the prion variant (
      • Tanaka M.
      • Chien P.
      • Naber N.
      • Cooke R.
      • Weissman J.S.
      Conformational variations in an infectious protein determine prion strain differences.
      ,
      • Bradley M.E.
      • Liebman S.W.
      The Sup35 domains required for maintenance of weak, strong or undifferentiated yeast [PSI+] prions.
      ,
      • Chang H.-Y.
      • Lin J.-Y.
      • Lee H.-C.
      • Wang H.-L.
      • King C.-Y.
      Strain-specific sequences required for yeast prion [PSI+] propagation.
      ). The “prion domains” have normal nonprion functions. The Ure2p prion domain is necessary for the stability of the whole molecule against degradation, and thus for the full nitrogen regulation function (
      • Shewmaker F.
      • Mull L.
      • Nakayashiki T.
      • Masison D.C.
      • Wickner R.B.
      Ure2p function is enhanced by its prion domain in Saccharomyces cerevisiae.
      ). The prion domain of Sup35p is necessary for general turnover of mRNAs (
      • Hosoda N.
      • Kobayashi T.
      • Uchida N.
      • Funakoshi Y.
      • Kikuchi Y.
      • Hoshino S.
      • Katada T.
      Translation termination factor eRF3 mediates mRNA decay through the regulation of deadenylation.
      ), for cytoskeleton-associated translation (
      • Li X.
      • Rayman J.B.
      • Kandel E.R.
      • Derkatch I.L.
      Functional role of Tia1/Pub1 and Sup35 prion domains: directing protein synthesis machinery to the tubulin cytoskeleton.
      ), and for recovery from the stationary phase (
      • Franzmann T.M.
      • Jahnel M.
      • Pozniakovsky A.
      • Mahamid J.
      • Holehouse A.S.
      • Nüske E.
      • Richter D.
      • Baumeister W.
      • Grill S.W.
      • Pappu R.V.
      • Hyman A.A.
      • Alberti S.
      Phase separation of a yeast protein promotes cellular fitness.
      ).

      Structure of infectious yeast prion amyloids

      In an attempt to show that there were sequences in the prion domains of Ure2p and Sup35p needed for prion formation, it was, surprisingly, found that randomly shuffling these domains produced sequences that in all cases were able to form prions (
      • Ross E.D.
      • Baxa U.
      • Wickner R.B.
      Scrambled prion domains form prions and amyloid.
      ,
      • Ross E.D.
      • Edskes H.K.
      • Terry M.J.
      • Wickner R.B.
      Primary sequence independence for prion formation.
      • Ross E.D.
      • Minton A.
      • Wickner R.B.
      Prion domains: sequences, structures and interactions.
      )! This proved that it was not the sequence but rather the amino acid content of these domains that made them suitable for prion formation, and detailed analysis has revealed which residues favor or impair prion formation (
      • Toombs J.A.
      • Liss N.M.
      • Cobble K.R.
      • Ben-Musa Z.
      • Ross E.D.
      [PSI+] maintenance is dependent on the composition, not the primary sequence, of the oligopeptide repeat domain.
      ,
      • Toombs J.A.
      • McCarty B.R.
      • Ross E.D.
      Compositional determinants of prion formation in yeast.
      ). The sequence independence of prion formation, combined with the well-known barriers to prion propagation produced by even a single amino acid difference in some cases (
      • Doel S.M.
      • McCready S.J.
      • Nierras C.R.
      • Cox B.S.
      The dominant PNM2 mutation which eliminates the [PSI] factor of Saccharomyces cerevisiae is the result of a missense mutation in the SUP35 gene.
      ,
      • DePace A.H.
      • Santoso A.
      • Hillner P.
      • Weissman J.S.
      A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion.
      • King C.Y.
      Supporting the structural basis of prion strains: induction and identification of [PSI] variants.
      ), indicated that the faithful propagation of prion variant/strain information was not based on “complementarity,” as for DNA or RNA, but rather a principle of “identity” (
      • Ross E.D.
      • Minton A.
      • Wickner R.B.
      Prion domains: sequences, structures and interactions.
      ). Any complementarity feature (self-complementarity in this case) would be destroyed by shuffling the sequence. It was realized that an anti-parallel β-sheet, a β-helix, or an out-of-register parallel β-sheet would rely on complementarity between neighboring amino acids in different molecules (
      • Ross E.D.
      • Minton A.
      • Wickner R.B.
      Prion domains: sequences, structures and interactions.
      ). However, a parallel, in-register β-sheet features rows of identical amino acid residues along the long axis of the filament, such as had already been shown for Aβ amyloid (
      • Antzutkin O.N.
      • Balbach J.J.
      • Leapman R.D.
      • Rizzo N.W.
      • Reed J.
      • Tycko R.
      Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of β-sheets in Alzheimer’s β-amyloid fibrils.
      ). Shuffling the sequence would not prevent identical residues from interacting in a parallel in-register structure, only their order would change. For this reason, we proposed that the prion amyloids of Ure2p and Sup35p had an in-register parallel β-sheet architecture (
      • Ross E.D.
      • Minton A.
      • Wickner R.B.
      Prion domains: sequences, structures and interactions.
      ).
      Based on extensive studies of highly infectious amyloids of Sup35p, Ure2p, and Rnq1p, using solid-state NMR (
      • Shewmaker F.
      • Wickner R.B.
      • Tycko R.
      Amyloid of the prion domain of Sup35p has an in-register parallel β-sheet structure.
      • Baxa U.
      • Wickner R.B.
      • Steven A.C.
      • Anderson D.E.
      • Marekov L.N.
      • Yau W.-M.
      • Tycko R.
      Characterization of β-sheet structure in Ure2p1–89 yeast prion fibrils by solid state nuclear magnetic resonance.
      ,
      • Wickner R.B.
      • Dyda F.
      • Tycko R.
      Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register β-sheet structure.
      ,
      • Shewmaker F.
      • Kryndushkin D.
      • Chen B.
      • Tycko R.
      • Wickner R.B.
      Two prion variants of Sup35p have in-register β-sheet structures, independent of hydration.
      • Gorkovskiy A.
      • Thurber K.R.
      • Tycko R.
      • Wickner R.B.
      Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid.
      ) and EM (particularly mass/length measurements) (
      • Diaz-Avalos R.
      • King C.Y.
      • Wall J.
      • Simon M.
      • Caspar D.L.
      Strain-specific morphologies of yeast prion amyloids.
      ,
      • Baxa U.
      • Taylor K.L.
      • Wall J.S.
      • Simon M.N.
      • Cheng N.
      • Wickner R.B.
      • Steven A.
      Architecture of Ure2p prion filaments: the N-terminal domain forms a central core fiber.
      • Chen B.
      • Thurber K.R.
      • Shewmaker F.
      • Wickner R.B.
      • Tycko R.
      Measurement of amyloid fibril mass-per-length by tilted-beam transmission electron microscopy.
      ), it is clear that each of these prion amyloids in fact does have a folded, parallel, in-register, β-sheet architecture. Indeed, the amyloids formed by the shuffled prion domains also had this architecture (
      • Shewmaker F.
      • Ross E.D.
      • Tycko R.
      • Wickner R.B.
      Amyloids of shuffled prion domains that form prions have a parallel in-register β-sheet structure.
      ).

      Mechanism of conformational templating

      The fact that a single protein sequence can be the basis for an array of prion variants apparently differing only in protein conformation implies that there must be a mechanism for proteins to template their conformation and to transmit this conformation information to other molecules of the same sequence. This is the central mystery of prions. Based on the folded in-register parallel β-sheet architecture of yeast prion amyloids, we have suggested that the same forces of favorable interaction between identical side chains that keeps this architecture in-register also ensures that a new molecule joining the end of a filament will adopt the same structure as molecules already in the filament (Fig. 1) (
      • Wickner R.B.
      • Shewmaker F.
      • Kryndushkin D.
      • Edskes H.K.
      Protein inheritance (prions) based on parallel in-register β-sheet amyloid structures.
      ,
      • Wickner R.B.
      • Edskes H.K.
      • Bateman D.A.
      • Kelly A.C.
      • Gorkovskiy A.
      • Dayani Y.
      • Zhou A.
      Amyloids and yeast prion biology.
      ). A line of glutamine residues along the long axis of a filament can form a line of hydrogen bonds, but only if the molecules are in-register. Thus, this interaction stabilizes the in-register architecture. The same is true of a line of asparagines, serines, or threonines. A line of identical hydrophobic residues can have a series of stabilizing hydrophobic interactions if the structure is in-register. Charged residues would of course destabilize an in-register structure, and charged residues are rare in the prion domains of Ure2p, Sup35p, and Rnq1p. Furthermore, mutations blocking prion transmission are often uncharged-to-charged amino acid changes (
      • Doel S.M.
      • McCready S.J.
      • Nierras C.R.
      • Cox B.S.
      The dominant PNM2 mutation which eliminates the [PSI] factor of Saccharomyces cerevisiae is the result of a missense mutation in the SUP35 gene.
      ,
      • DePace A.H.
      • Santoso A.
      • Hillner P.
      • Weissman J.S.
      A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion.
      ). A molecule of the prion protein joining the end of the filament, to have these favorable side-chain interactions, must have a turn between the β-strands at the same location as those molecules already in the filament. This results in the end of the filament acting as a template to transmit conformation information to the new molecule joining the end of the filament (
      • Wickner R.B.
      • Shewmaker F.
      • Kryndushkin D.
      • Edskes H.K.
      Protein inheritance (prions) based on parallel in-register β-sheet amyloid structures.
      ,
      • Wickner R.B.
      • Edskes H.K.
      • Bateman D.A.
      • Kelly A.C.
      • Gorkovskiy A.
      • Dayani Y.
      • Zhou A.
      Amyloids and yeast prion biology.
      ). This templating explains how proteins can act as genes, templating conformation in analogy to the templating of sequence by replicating DNA or RNA (Fig. 1).
      Figure thumbnail gr1
      Figure 1A, folded parallel in-register β-sheet architecture of yeast prion amyloids Sup35p, Ure2p, and Rnq1p (
      • Shewmaker F.
      • Wickner R.B.
      • Tycko R.
      Amyloid of the prion domain of Sup35p has an in-register parallel β-sheet structure.
      ,
      • Baxa U.
      • Wickner R.B.
      • Steven A.C.
      • Anderson D.E.
      • Marekov L.N.
      • Yau W.-M.
      • Tycko R.
      Characterization of β-sheet structure in Ure2p1–89 yeast prion fibrils by solid state nuclear magnetic resonance.
      • Wickner R.B.
      • Dyda F.
      • Tycko R.
      Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register β-sheet structure.
      ,
      • Gorkovskiy A.
      • Thurber K.R.
      • Tycko R.
      • Wickner R.B.
      Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid.
      ). It is proposed that prion variants differ largely in the location of the turns in the strands/folds in the β-sheet (B), with favorable H-bonding or hydrophobic interactions among aligned side chains ensuring alignment of identical residues in adjacent molecules. These favorable interactions drive new molecules joining the end of the filament to have their turns in the same places as molecules already in the filament, and this constitutes templating of conformation (
      • Wickner R.B.
      • Shewmaker F.
      • Kryndushkin D.
      • Edskes H.K.
      Protein inheritance (prions) based on parallel in-register β-sheet amyloid structures.
      ,
      • Wickner R.B.
      • Edskes H.K.
      • Bateman D.A.
      • Kelly A.C.
      • Gorkovskiy A.
      • Dayani Y.
      • Zhou A.
      Amyloids and yeast prion biology.
      ). Reprinted with permission from Ref.
      • Wickner R.B.
      • Edskes H.K.
      • Bateman D.A.
      • Kelly A.C.
      • Gorkovskiy A.
      • Dayani Y.
      • Zhou A.
      Amyloids and yeast prion biology.
      . This research was originally published in Biochemistry. Wickner, R. B., Edskes, H. K., Bateman, D. A., Kelly, A. C., Gorkovskiy, A., Dayani, Y., and Zhou, A. Amyloids and yeast prion biology. Biochemistry 2013;52:1514–1527. © the American Chemical Society.
      Nearly all of the pathogenic amyloids associated with human diseases that have been examined have the same folded in-register parallel β-sheet architecture (
      • Antzutkin O.N.
      • Balbach J.J.
      • Leapman R.D.
      • Rizzo N.W.
      • Reed J.
      • Tycko R.
      Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of β-sheets in Alzheimer’s β-amyloid fibrils.
      ,
      • Der-Sarkissian A.
      • Jao C.C.
      • Chen J.
      • Langen R.
      Structural organization of α-synuclein fibrils studied by site-directed spin labeling.
      • Margittai M.
      • Langen R.
      Template-assisted filament growth by parallel stacking of tau.
      ,
      • Cobb N.J.
      • Sönnichsen F.D.
      • McHaourab H.
      • Surewicz W.K.
      Molecular architecture of human prion protein amyloid: a parallel, in-register β-structure.
      ,
      • Luca S.
      • Yau W.-M.
      • Leapman R.
      • Tycko R.
      Peptide conformation and supramolecular organization in amylin fibrils: constraints from solid-state NMR.
      ,
      • Tycko R.
      • Savtchenko R.
      • Ostapchenko V.G.
      • Makarava N.
      • Baskakov I.V.
      The α-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel β-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance.
      ,
      • Ladner C.L.
      • Chen M.
      • Smith D.P.
      • Platt G.W.
      • Radford S.E.
      • Langen R.
      Stacked sets of parallel, in-register β-strands of β2-microglobulin in amyloid fibrils revealed by site-directed spin labeling and chemical labeling.
      ,
      • Groveman B.R.
      • Dolan M.A.
      • Taubner L.M.
      • Kraus A.
      • Wickner R.B.
      • Caughey B.
      Parallel in-register intermolecular β sheet architecture for prion seeded PrP amyloids.
      • Tuttle M.D.
      • Comellas G.
      • Nieuwkoop A.J.
      • Covell D.J.
      • Berthold D.A.
      • Kloepper K.D.
      • Courtney J.M.
      • Kim J.K.
      • Barclay A.M.
      • Kendall A.
      • Wan W.
      • Stubbs G.
      • Schwieters C.D.
      • Lee V.M.
      • George J.M.
      • Rienstra C.M.
      Solid-state NMR structure of a pathogenic fibril of a full-length human α-synuclein.
      ) as observed for these yeast prions, with one exception being transthyretin (
      • Blake C.
      • Serpell L.
      Synchrotron x-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous β-sheet helix.
      ,
      • Serag A.A.
      • Altenbach C.
      • Gingery M.
      • Hubbell W.L.
      • Yeates T.O.
      Arrangement of subunits and ordering of β-strands in an amyloid sheet.
      • Bateman D.A.
      • Tycko R.
      • Wickner R.B.
      Experimentally derived structural constraints for amyloid fibrils of wild-type transthyretin.
      ). It is likely that templating of conformational information for the human pathologic amyloids proceeds by the same mechanism discussed here.

      Yeast prions [PSI+], [URE3], [SWI+], and [PIN+] are pathogenic

      Most variants of [PSI+] and [URE3] arising in WT laboratory strains severely slow growth or actually kill the host cells (
      • McGlinchey R.P.
      • Kryndushkin D.
      • Wickner R.B.
      Suicidal [PSI+] is a lethal yeast prion.
      ). A beneficial prion variant would be widespread in wild strains, particularly because they are infectious, but [PSI+], [URE3], [SWI+], and [PIN+] are known to be rare in wild isolates (
      • Nakayashiki T.
      • Kurtzman C.P.
      • Edskes H.K.
      • Wickner R.B.
      Yeast prions [URE3] and [PSI+] are diseases.
      ,
      • Bateman D.A.
      • Wickner R.B.
      [PSI+] prion transmission barriers protect Saccharomyces cerevisiae from infection: intraspecies 'species barriers'.
      • Halfmann R.
      • Jarosz D.F.
      • Jones S.K.
      • Chang A.
      • Lancaster A.K.
      • Lindquist S.
      Prions are a common mechanism for phenotypic inheritance in wild yeasts.
      ), more rare than the 2-μm DNA plasmid that is known to cause a >1% growth detriment (
      • Nakayashiki T.
      • Kurtzman C.P.
      • Edskes H.K.
      • Wickner R.B.
      Yeast prions [URE3] and [PSI+] are diseases.
      ,
      • Kelly A.C.
      • Shewmaker F.P.
      • Kryndushkin D.
      • Wickner R.B.
      Sex, prions and plasmids in yeast.
      ). These and other results show that no variants of these prions are beneficial on the net (
      • Wickner R.B.
      • Shewmaker F.P.
      • Bateman D.A.
      • Edskes H.K.
      • Gorkovskiy A.
      • Dayani Y.
      • Bezsonov E.E.
      Yeast prions: structure, biology and prion-handling systems.
      ).

      Anti-prion systems in yeast

      There is a wide array of cellular components whose overproduction or deficiency leads to the loss of one or another prion (
      • Liebman S.W.
      • Chernoff Y.O.
      Prions in yeast.
      ,
      • Masison D.C.
      • Reidy M.
      Yeast prions are useful for studying protein chaperones and protein quality control.
      ,
      • Wickner R.B.
      • Bezsonov E.E.
      • Son M.
      • Ducatez M.
      • DeWilde M.
      • Edskes H.K.
      Anti-prion systems in yeast and inositol polyphosphates.
      ). These studies have been important in establishing mechanisms affecting prions, but it is generally unclear which of these effects represent physiologic (or pathophysiologic) responses of cells to prions. It is of particular interest to know whether there are systems that cure yeast prions in a normal cell, without overproduction or deletion of anything, and it is these that we refer to as “anti-prion” systems. As expected for a pathogenic infectious agent, the cell indeed has defenses against yeast prions at several levels. Prion formation is partially blocked; having formed, several systems cure the nascent prions; and other systems prevent prion-based pathology (Table 1). As with DNA repair systems, these anti-prion systems are each only partially effective.
      Table 1Yeast anti-prion systems active without overexpression or deficiency
      Anti-prion proteinAnti-prion protein activityPrion affectedEffectRef.
      Ssb1p, Ssb2pRibosome-associated Hsp70[PSI+]Prevents [PSI+] formation
      • Chernoff Y.O.
      • Newnam G.P.
      • Kumar J.
      • Allen K.
      • Zink A.D.
      Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone Ssb in formation, stability and toxicity of the [PSI] prion.
      ,
      • Kiktev D.A.
      • Melomed M.M.
      • Lu C.D.
      • Newnam G.P.
      • Chernoff Y.O.
      Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.
      ,
      • Chacinska A.
      • Szczesniak B.
      • Kochneva-Pervukhova N.V.
      • Kushnirov V.V.
      • Ter-Avanesyan M.D.
      • Boguta M.
      Ssb1 chaperone is a [PSI+] prion-curing factor.
      Btn2pCollector of aggregates[URE3]Cures by sequestration of amyloid filaments
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ,
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      Cur1p??[URE3]Cures by unknown mechanism
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ,
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ,
      • Barbitoff Y.A.
      • Matveenko A.G.
      • Moskalenko S.E.
      • Zemlyanko O.M.
      • Newnam G.P.
      • Patel A.
      • Chernova T.A.
      • Chernoff Y.O.
      • Zhouravleva G.A.
      To CURe or not to CURe? Differential effects of the chaperone sorting factor Cur1 on yeast prions are mediated by the chaperone Sis1.
      Hsp104Disaggregating chaperone[PSI+]Cures–mechanism controversial: asymmetric segregation or blocking Hsp70 access for filament cleavage
      • Chernoff Y.O.
      • Lindquist S.L.
      • Ono B.
      • Inge-Vechtomov S.G.
      • Liebman S.W.
      Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+].
      ,
      • Helsen C.W.
      • Glover J.R.
      Insight into molecular basis of curing of [PSI+] prion by overexpression of 104-kDa heat shock protein (Hsp104).
      ,
      • Winkler J.
      • Tyedmers J.
      • Bukau B.
      • Mogk A.
      Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation.
      • Ness F.
      • Cox B.S.
      • Wonwigkarm J.
      • Naeimi W.R.
      • Tuite M.F.
      Over-expression of the molecular chaperone Hsp104 in Saccharomyces cerevisiae results in the malpartition of [PSI+] propagons.
      ,
      • Gorkovskiy A.
      • Reidy M.
      • Masison D.C.
      • Wickner R.B.
      Hsp104 at normal levels cures many [PSI+] variants in a process promoted by Sti1p, Hsp90 and Sis1p.
      Siw14p5-Pyrophosphate-inositol-hexakisphosphate pyrophosphatase[PSI+]Cures by lowering 5PP-IP5 levels
      • Wickner R.B.
      • Kelly A.C.
      • Bezsonov E.E.
      • Edskes H.K.
      Prion propagation is controlled by inositol polyphosphates.
      ,
      • Steidle E.A.
      • Chong L.S.
      • Wu M.
      • Crooke E.
      • Fiedler D.
      • Resnick A.C.
      • Rolfes R.J.
      A novel inositol pyrophosphate phosphatase in Saccharomyces cerevisiae: Siw14 protein selectively cleaves the β-phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP5).
      Upf1p, Upf2p, Upf3pNonsense-mediated mRNA decay factors[PSI+]Cures, perhaps by either binding Sup35p monomers or binding to filaments blocking extension
      • Son M.
      • Wickner R.B.
      Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants.
      Sis1pHsp40 chaperone[PSI+]Prevents lethality of normally mild variant
      • Kirkland P.A.
      • Reidy M.
      • Masison D.C.
      Functions of yeast Hsp40 chaperone Sis1p dispensable for prion propagation but important for prion curing and protection from prion toxicity.
      Lug1p/YRL352wpF-box protein; substrate-specifying subunit of cullin ubiquitin ligase[URE3]Allows growth of [URE3] strains on glycerol
      • Edskes H.K.
      • Mukhamedova M.
      • Edskes B.K.
      • Wickner R.B.
      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.

      Ribosome-associated Hsp70s inhibit [PSI+] formation

      Ssb1 and Ssb2 are Hsp70 family members that are associated with the ribosomes and are involved in folding of nascent polypeptides (
      • Pfund C.
      • Lopez-Hoyo N.
      • Ziegelhoffer T.
      • Schilke B.A.
      • Lopez-Buesa P.
      • Walter W.A.
      • Wiedmann M.
      • Craig E.A.
      The molecular chaperone Ssb from Saccharomyces cerevisiae is a component of the ribosome-nascent chain complex.
      ,
      • Chernoff Y.O.
      • Kiktev D.A.
      Dual role of ribosome-associated chaperones in prion formation and propagation.
      ). For example, in the absence of the Ssb proteins, aggregated proteins accumulate in the cell (
      • Koplin A.
      • Preissler S.
      • Ilina Y.
      • Koch M.
      • Scior A.
      • Erhardt M.
      • Deuerling E.
      A dual function for chaperones SSB-RAC and the NAC nascent polypeptide-associated complex on ribosomes.
      ). In ssb1Δ ssb2Δ cells, the frequency of [PSI+] arising is about 10-fold higher than in a normal cell (
      • Chernoff Y.O.
      • Newnam G.P.
      • Kumar J.
      • Allen K.
      • Zink A.D.
      Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone Ssb in formation, stability and toxicity of the [PSI] prion.
      ,
      • Amor A.J.
      • Castanzo D.T.
      • Delany S.P.
      • Selechnik D.M.
      • van Ooy A.
      • Cameron D.M.
      The ribosome-associated complex antagonizes prion formation in yeast.
      ). Restoration of Ssb1 does not cure the [PSI+] variants arising in the double mutant, indicating that the Ssb proteins largely prevent [PSI+] generation, rather than blocking their propagation (
      • Chernoff Y.O.
      • Newnam G.P.
      • Kumar J.
      • Allen K.
      • Zink A.D.
      Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone Ssb in formation, stability and toxicity of the [PSI] prion.
      ). However, dissociation of Ssb’s from ribosomes in cells grown on minimal medium has a [PSI+]-curing effect (
      • Kiktev D.A.
      • Melomed M.M.
      • Lu C.D.
      • Newnam G.P.
      • Chernoff Y.O.
      Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.
      ).

      Hsp40 family member Sis1p prevents toxicity of otherwise mild [PSI+] prion variants

      Although a majority of [PSI+] prion variants are highly toxic to cells, the variants usually studied do not produce an obvious growth defect. The studies of wild strains (above) show that even these variants are detrimental in the wild. However, Masison’s group (
      • Kirkland P.A.
      • Reidy M.
      • Masison D.C.
      Functions of yeast Hsp40 chaperone Sis1p dispensable for prion propagation but important for prion curing and protection from prion toxicity.
      ) has shown that these “mild” [PSI+] variants have the potential to prevent cell growth except for the action of the Sis1p protein. Sis1p is essential for growth, but deletion of the C-terminal domain of the protein does not substantially affect growth of [psi−] cells. However, [PSI+] cells with the Sis1p C-terminal deletion grow poorly or not at all (
      • Kirkland P.A.
      • Reidy M.
      • Masison D.C.
      Functions of yeast Hsp40 chaperone Sis1p dispensable for prion propagation but important for prion curing and protection from prion toxicity.
      ).

      F-box protein Ylr352w/Lug1 prevents toxicity of mild [URE3]

      A general screen for genes that are essential specifically in [URE3] cells was carried out using transposon mutagenesis with the Hermes transposon (
      • Edskes H.K.
      • Mukhamedova M.
      • Edskes B.K.
      • Wickner R.B.
      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.
      ). Genes that could be mutated in a [ure-o] cell, but not in a [URE3−1] strain, were inferred to be either necessary for propagation of [URE3] or for cell growth/survival in the presence of the prion. The most dramatic hit from the screen was YLR352W (renamed LUG1 for “lets [URE3] grow”) (
      • Edskes H.K.
      • Mukhamedova M.
      • Edskes B.K.
      • Wickner R.B.
      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.
      ), encoding a substrate-specifying subunit of a cullin-containing multisubunit E3 ubiquitin ligase (
      • Seol J.H.
      • Shevchenko A.
      • Shevchenko A.
      • Deshaies R.J.
      Skip1 forms multiple protein complexes, including RAVE, a regulator of V-ATPase assembly.
      ). Other subunits of this complex and subunit-modifying proteins also were detected in the screen (
      • Edskes H.K.
      • Mukhamedova M.
      • Edskes B.K.
      • Wickner R.B.
      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.
      ). Lug1p is one of 20 substrate-specifying subunits with a common sequence called the “F-box” (
      • Seol J.H.
      • Shevchenko A.
      • Shevchenko A.
      • Deshaies R.J.
      Skip1 forms multiple protein complexes, including RAVE, a regulator of V-ATPase assembly.
      • Sarikas A.
      • Hartmann T.
      • Pan Z.Q.
      The cullin protein family.
      ,
      • Hua Z.
      • Vierstra R.D.
      The cullin-ring ubiquitin-protein ligases.
      • Jonkers W.
      • Rep M.
      Lessons from fungal F-box proteins.
      ), but the substrates specified by Lug1p are unknown. The lug1Δ [URE3] strains could not grow on glycerol media, whereas lug1Δ [ure-o] cells grew normally. The growth defect was suppressed by overproduction of Hap4p, a transcription factor that stimulates expression of mitochondria-related genes, consistent with the requirement for oxidation for utilization of glycerol (
      • Edskes H.K.
      • Mukhamedova M.
      • Edskes B.K.
      • Wickner R.B.
      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.
      ). The growth defect of lug1Δ [URE3] strains was also suppressed by mutation of GLN1, encoding glutamine synthase. Like cells carrying [URE3], gln1 mutants are defective in nitrogen catabolite repression, the diminished expression of genes for using poor nitrogen sources when a good nitrogen source is available. This indicates that the inability to utilize glycerol of the lug1 [URE3] strains was not a consequence of failure to control nitrogen catabolism. Growth of lug1Δ strains on proline, a condition that is known to shut off Ure2p’s activity in repressing NCR genes, does not affect cell growth, confirming the conclusion that Ure2p has another function independent of NCR (
      • Edskes H.K.
      • Mukhamedova M.
      • Edskes B.K.
      • Wickner R.B.
      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.
      ). It remains unclear what is the relevant target of Lug1p, but it is clear that this protein prevents the pathologic effects of an otherwise relatively mild variant of [URE3].
      The same screen also showed a substantial decrease in detection of mutations in many chaperone genes, including some that had not previously been implicated in [URE3] prion propagation. This effect was observed for HSP82 and HSC82 (encoding Hsp90 paralogs), HSP104 and SSA2 (known to be necessary for [URE3] propagation (
      • Moriyama H.
      • Edskes H.K.
      • Wickner R.B.
      [URE3] prion propagation in Saccharomyces cerevisiae: requirement for chaperone Hsp104 and curing by overexpressed chaperone Ydj1p.
      ,
      • Roberts B.T.
      • Moriyama H.
      • Wickner R.B.
      [URE3] prion propagation is abolished by a mutation of the primary cytosolic Hsp70 of budding yeast.
      )), YDJ1 and CAJ1 (Hsp40s), STI1 (co-chaperone of Hsp90s), FES1 and SSE1 (nucleotide exchange factors for Hsp70s known to affect [URE3] (
      • Kryndushkin D.
      • Wickner R.B.
      Nucleotide exchange factors for Hsp70s are required for [URE3] prion propagation in Saccharomyces cerevisiae.
      )), HSP26 and HSP42 (“small” heat-shock proteins), SSB1 and SSB2 (ribosome-associated Hsp70s), and SSA1 and SBA1. Whether these effects reflect specific toxicities of [URE3] prevented by the chaperones, or a synergistic toxicity of prion-induced stress and stress due to chaperone deficiency, remains to be determined. Nearly all of these chaperones have close human homologs (HSP104 is a notable exception), making understanding this phenomenon of particular interest.

      Normal levels of Btn2p and Cur1p cure most [URE3] variants

      Overproduction of either of two paralogs, Btn2p or Cur1p, cure [URE3] (
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ). In the process, Btn2p collects the aggregates of Ure2p at one site in the cell (instead of being scattered about the cytoplasm), and this collection spot co-localizes with a spot of Btn2p (
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ). Apparently, on cell division, the probability of daughter cells getting any filaments is thereby reduced, producing frequent cured cells (
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ). Consistent with this “sequestration model,” Btn2p can also collect nonprion aggregates of other proteins at a single cellular site (
      • Kryndushkin D.
      • Ihrke G.
      • Piermartiri T.C.
      • Shewmaker F.
      A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity.
      ,
      • Malinovska L.
      • Kroschwald S.
      • Munder M.C.
      • Richter D.
      • Alberti S.
      Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates.
      ). However, Cur1p did not co-localize with Ure2p aggregates in the course of its curing of [URE3] (
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ).
      To determine whether normal levels of Btn2p or Cur1p have an anti-prion action, a series of [URE3] prion variants was isolated in a btn2Δ cur1Δ strain, and the normal levels of each protein were restored by mating or by other means (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ). Remarkably, nearly all (∼90%) of these [URE3] variants were cured in the WT environment, although most were quite stable in the btn2Δ cur1Δ strain. Indeed, the frequency of [URE3] arising spontaneously was elevated about 5-fold in btn2Δ cur1Δ strains (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ). A propagon-measuring method (
      • Cox B.
      • Ness F.
      • Tuite M.
      Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast.
      ) revealed that variants of [URE3] with high seed number (presumably many amyloid filaments per cell) could only be cured by overproduction of Btn2p or Cur1p, whereas those variants with low seed numbers were cured by normal levels of these proteins (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ). Thus, there are far more prions arising than the few that manage to escape the cellular anti-prion systems.
      Btn2p overproduction curing of [URE3] requires Hsp42 (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ), a small chaperone also known to be involved in collecting nonprion aggregates of denatured proteins (
      • Specht S.
      • Miller S.B.
      • Mogk A.
      • Bukau B.
      Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae.
      ). Hsp42 overproduction can also cure [URE3] (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ). Btn2p overproduction curing of [URE3] does not require Cur1p nor does Cur1p overproduction curing require Btn2p (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ). The facts that Cur1p does not co-localize with Ure2p aggregates in the process of curing [URE3] (
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ) and that Cur1p overproduction curing does not require Hsp42 (
      • Wickner R.B.
      • Bezsonov E.
      • Bateman D.A.
      Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants.
      ) suggest that Cur1p and Btn2p cure by different mechanisms, despite their sequence similarity (
      • Barbitoff Y.A.
      • Matveenko A.G.
      • Moskalenko S.E.
      • Zemlyanko O.M.
      • Newnam G.P.
      • Patel A.
      • Chernova T.A.
      • Chernoff Y.O.
      • Zhouravleva G.A.
      To CURe or not to CURe? Differential effects of the chaperone sorting factor Cur1 on yeast prions are mediated by the chaperone Sis1.
      ).
      Btn2p was previously known as a mediator of protein trafficking in the endosome pathway (
      • Chattopadhyay S.
      • Pearce D.A.
      Interaction with Btn2p is required for localization of Rsg1p: Btn2p-mediated changes in arginine uptake in Saccharomyces cerevisiae.
      ,
      • Kama R.
      • Robinson M.
      • Gerst J.E.
      Btn2, a Hook1 ortholog and potential Batten disease-related protein, mediates late endosome-Golgi protein sorting in yeast.
      ), and Btn3p, an inhibitor of Btn2p's action in protein sorting, also inhibits its ability to sequester the [URE3] amyloid filaments and cure the prion (
      • Kanneganti V.
      • Kama R.
      • Gerst J.E.
      Btn3 is a negative regulator of Btn2-mediated endosomal protein trafficking and prion curing in yeast.
      ). This is the only connection yet defined between the protein-sorting and aggregate-collecting activities of Btn2p.

      Normal levels of the Hsp104 disaggregase cures most [PSI+] variants

      Hsp104 is a disaggregating chaperone that, in concert with Hsp40s and Hsp70s, disaggregates denatured proteins allowing cells to recover from heat shock (
      • Glover J.R.
      • Lindquist S.
      Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins.
      ). Hsp104, working with Hsp70s, Hsp40s, and nucleotide exchange factors, cleaves prion amyloid filaments to generate new filament ends and thus new growing points (
      • Paushkin S.V.
      • Kushnirov V.V.
      • Smirnov V.N.
      • Ter-Avanesyan M.D.
      Propagation of the yeast prion-like [psi+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor.
      ,
      • Masison D.C.
      • Reidy M.
      Yeast prions are useful for studying protein chaperones and protein quality control.
      ,
      • Chernoff Y.O.
      • Lindquist S.L.
      • Ono B.
      • Inge-Vechtomov S.G.
      • Liebman S.W.
      Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+].
      • Wegrzyn R.D.
      • Bapat K.
      • Newnam G.P.
      • Zink A.D.
      • Chernoff Y.O.
      Mechanism of prion loss after Hsp104 inactivation in yeast.
      ,
      • Winkler J.
      • Tyedmers J.
      • Bukau B.
      • Mogk A.
      Chaperone networks in protein disaggregation and prion propagation.
      • Matveenko A.G.
      • Barbitoff Y.A.
      • Jay-Garcia L.M.
      • Chernoff Y.O.
      • Zhouravleva G.A.
      Differential effects of chaperones on yeast prions: CURrent views.
      ,
      • Reidy M.
      • Miot M.
      • Masison D.C.
      Prokaryotic chaperones support yeast prions and thermotolerance and define disaggregation machinery interactions.
      ). However, overproduction of Hsp104 cures the [PSI+] prion (
      • Chernoff Y.O.
      • Lindquist S.L.
      • Ono B.
      • Inge-Vechtomov S.G.
      • Liebman S.W.
      Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+].
      ) and [URE3] to a minor extent (
      • Kryndushkin D.S.
      • Shewmaker F.
      • Wickner R.B.
      Curing of the [URE3] prion by Btn2p, a Batten disease-related protein.
      ). The propagation-promoting activity of Hsp104 involves its removing monomers from the middle of an amyloid filament thereby breaking it into two pieces (
      • Ness F.
      • Ferreira P.
      • Cox B.S.
      • Tuite M.F.
      Guanidine hydrochloride inhibits the generation of prion “seeds” but not prion protein aggregation in yeast.
      ,
      • Mogk A.
      • Kummer E.
      • Bukau B.
      Cooperation of Hsp70 and Hsp100 chaperone machines in protein disaggregation.
      ). Inhibition of Hsp104 by millimolar concentrations of guanidine results in the arrest of new filament formation, and eventual curing of the prion in most progeny cells as the filaments are diluted by cell growth (
      • Cox B.
      • Ness F.
      • Tuite M.
      Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast.
      ,
      • Jung G.
      • Masison D.C.
      Guanidine hydrochloride inhibits Hsp104 activity in vivo: a possible explanation for its effect in curing yeast prions.
      ,
      • Ferreira P.C.
      • Ness F.
      • Edwards S.R.
      • Cox B.S.
      • Tuite M.F.
      The elimination of the yeast [PSI+] prion by guanidine hydrochloride is the result of Hsp104 inactivation.
      • Jung G.
      • Jones G.
      • Masison D.C.
      Amino acid residue 184 of yeast Hsp104 chaperone is critical for prion-curing by guanidine, prion propagation, and thermotolerance.
      ).
      The mechanism of the [PSI+]-curing effect of Hsp104 overproduction is still controversial, despite extensive study. One line of evidence shows that Hsp104 has a specific binding site in the M (middle) domain of Sup35p (
      • Helsen C.W.
      • Glover J.R.
      Insight into molecular basis of curing of [PSI+] prion by overexpression of 104-kDa heat shock protein (Hsp104).
      ) and that excessive Hsp104 blocks access of Hsp70s to the filaments, thereby preventing filament cleavage (
      • Winkler J.
      • Tyedmers J.
      • Bukau B.
      • Mogk A.
      Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation.
      ). Another study shows that overproduced Hsp104 results in asymmetric segregation of prion seeds, resulting in frequent loss of the prion (
      • Ness F.
      • Cox B.S.
      • Wonwigkarm J.
      • Naeimi W.R.
      • Tuite M.F.
      Over-expression of the molecular chaperone Hsp104 in Saccharomyces cerevisiae results in the malpartition of [PSI+] propagons.
      ). A third group proposes that the overproduction curing activity of Hsp104 is a “trimming” activity, removing monomers from the ends (in contrast to cleavage of filaments in the middle) (
      • Greene L.E.
      • Zhao X.
      • Eisenberg E.
      Curing of [PSI+] by Hsp104 overexpression: clues to solving the puzzle.
      ).
      To determine whether normal levels of Hsp104 cure some [PSI+] variants as they arise, we used the same approach as discussed above for Btn2 and Cur1. We used the hsp104T160M mutant that propagates [PSI+] normally but cannot cure [PSI+] even if overproduced (
      • Hung G.C.
      • Masison D.C.
      N-terminal domain of yeast Hsp104 chaperone is dispensable for thermotolerance and prion propagation but necessary for curing prions by Hsp104 overexpression.
      ). A series of [PSI+] variants isolated in this strain was tested for the ability to propagate in an HSP104 host, and about half were unable to do so (
      • Gorkovskiy A.
      • Reidy M.
      • Masison D.C.
      • Wickner R.B.
      Hsp104 at normal levels cures many [PSI+] variants in a process promoted by Sti1p, Hsp90 and Sis1p.
      ). The frequency of [PSI+] arising spontaneously was elevated over 10-fold in hsp104T160M hosts. These results indicate that the normal Hsp104 (without overexpression) cures many [PSI+] variants as they arise (
      • Gorkovskiy A.
      • Reidy M.
      • Masison D.C.
      • Wickner R.B.
      Hsp104 at normal levels cures many [PSI+] variants in a process promoted by Sti1p, Hsp90 and Sis1p.
      ).

      Inositol pyro-/polyphosphates and [PSI+] propagation

      In a general screen of the knockout collection for mutants defective in anti-[PSI+] activity, two isolates were siw14::kanMX mutants (
      • Wickner R.B.
      • Kelly A.C.
      • Bezsonov E.E.
      • Edskes H.K.
      Prion propagation is controlled by inositol polyphosphates.
      ), lacking a pyrophosphatase specifically active on 5-pyrophosphoinositol pentakisphosphate, and thus having elevated levels of this compound (Fig. 2) (
      • Steidle E.A.
      • Chong L.S.
      • Wu M.
      • Crooke E.
      • Fiedler D.
      • Resnick A.C.
      • Rolfes R.J.
      A novel inositol pyrophosphate phosphatase in Saccharomyces cerevisiae: Siw14 protein selectively cleaves the β-phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP5).
      ). We found that nearly all [PSI+] variants require some inositol poly/pyrophosphate and that 5-pyrophosphoinositol tetrakisphosphate, inositol hexakisphosphate, or 5-pyrophosphoinositol pentakisphosphate could support [PSI+] propagation (
      • Wickner R.B.
      • Kelly A.C.
      • Bezsonov E.E.
      • Edskes H.K.
      Prion propagation is controlled by inositol polyphosphates.
      ). In the absence of the 5-pyrophosphoinositol polyphosphates, elevated levels of the 1-pyrophosphoinositol polyphosphates inhibited [PSI+] propagation (
      • Wickner R.B.
      • Kelly A.C.
      • Bezsonov E.E.
      • Edskes H.K.
      Prion propagation is controlled by inositol polyphosphates.
      ). The target(s) of the inositol poly/pyrophosphates in exerting these effects is at this time unclear. The inositol poly/pyrophosphates have a wide array of activities (
      • Shears S.B.
      Intimate connections: inositol pyrophosphates at the interface of metabolic regulation and cell signaling.
      ,
      • Hatch A.J.
      • Odom A.R.
      • York J.D.
      Inositol phosphate multikinase dependent transcriptional control.
      ), making this a difficult task. Wu et al. (
      • Wu M.
      • Chong L.S.
      • Perlman D.H.
      • Resnick A.C.
      • Fiedler D.
      Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms.
      ) prepared affinity resins with the inositol poly/pyrophosphates that support [PSI+] and identified yeast proteins that adhere to columns of these resins. Among these were Hsp26p, Sse1p, and Ssb1,2, each of which has been reported to affect [PSI+] generation or propagation (
      • Chernoff Y.O.
      • Newnam G.P.
      • Kumar J.
      • Allen K.
      • Zink A.D.
      Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone Ssb in formation, stability and toxicity of the [PSI] prion.
      ,
      • Kryndushkin D.
      • Wickner R.B.
      Nucleotide exchange factors for Hsp70s are required for [URE3] prion propagation in Saccharomyces cerevisiae.
      ,
      • Fan Q.
      • Park K.-W.
      • Du Z.
      • Morano K.A.
      • Li L.
      The role of Sse1 in the de novo formation and variant determination of the [PSI+] prion.
      ,
      • Duennwald M.L.
      • Echeverria A.
      • Shorter J.
      Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans.
      ), and they must be considered candidates for mediators of action of the inositol poly/pyrophosphates.
      Figure thumbnail gr2
      Figure 2Inositol pyro/polyphosphate pathways showing [PSI+]-supporting (green arrows) and [PSI+]-inhibiting (red symbol) species (modified from Ref.
      • Wickner R.B.
      • Kelly A.C.
      • Bezsonov E.E.
      • Edskes H.K.
      Prion propagation is controlled by inositol polyphosphates.
      ). IP3, inositol 1,4,5-trisphosphate; IP4, inositol tetrakisphosphate; 5PP-IP5, 5-diphosphoinositol pentakisphosphate; IP6, inositol 1,2,3,4,5,6-hexakisphosphate.

      Upf proteins, mediators of nonsense-mediated mRNA decay, cure many [PSI+] variants

      The screen described above also returned deletions of UPF1 and UPF3 (
      • Son M.
      • Wickner R.B.
      Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants.
      ), genes encoding components of the nonsense-mediated mRNA decay apparatus, responsible for elimination of mRNAs carrying a premature stop codon (
      • He F.
      • Jacobson A.
      Nonsense-mediated mRNA decay: degradation of defective transcripts is only part of the story.
      ). Because these genes also affect the genetic test for [PSI+] (readthrough of a premature stop codon), it was shown in several different ways that the effect of the Upf proteins was on prion propagation and not on the assay. The upf mutants have a >10-fold increased frequency of [PSI+] generation, and nearly all of the [PSI+] variants produced in a upf mutant are cured by simply replacing the normal amount of the Upf protein (
      • Son M.
      • Wickner R.B.
      Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants.
      ). The Upf proteins normally form a complex with the translation termination factors Sup35p and Sup45p on the ribosome, and it is argued that this complex stabilizes Sup35p in its normal form preventing conversion to the amyloid form (
      • Son M.
      • Wickner R.B.
      Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants.
      ). Upf1p, at sub-stoichiometric levels, inhibits amyloid formation in vitro by Sup35p (but not by Ure2p), suggesting that a direct interaction is responsible for blocking prion propagation (
      • Son M.
      • Wickner R.B.
      Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants.
      ). Examination of a series of UPF1 and UPF2 mutants showed a poor correlation of [PSI+]-curing activity (
      • Son M.
      • Wickner R.B.
      Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants.
      ) with nonsense-mediated decay (NMD) efficiency, RNA helicase, ATPase, or RNA-binding activity, but a better correlation with their reported (
      • Weng Y.
      • Czaplinski K.
      • Peltz S.W.
      Genetic and biochemical characterization of mutations in the ATPase and helicase region of the Upf1 protein.
      ,
      • He F.
      • Ganesan R.
      • Jacobson A.
      Intra- and intermolecular regulatory interactions in Upf1p, the RNA helicase central to nonsense-mediated mRNA decay in yeast.
      ) formation of the Upf1–2-3 complex and binding to Sup35p.
      It is possible that the binding of Sup35p monomers by the Upf complex competes with their binding to amyloid filaments. Alternatively, the binding of the Upf1–2-3 complex to the ends of Sup35p amyloid filaments may block access of Sup35p monomers to these growth points. We infer that normal protein–protein interactions naturally compete with and may even reverse abnormal interactions. This may have general implications applicable to treatment of disease.

      Study of anti-prion systems reveals an unexpected abundance of prion variants

      At this time the various anti-prion systems appear to be specific for a particular prion, although only limited tests have been done. Several systems cure [PSI+] variants, and it is not yet known whether they work independently or in concert. It is evident in yeast that prions are arising at a dramatically higher rate than was previously appreciated and that the array of anti-prion systems cures most of them. There are also anti-prion systems that prevent prion formation, and others that make some of those prions that do succeed in arising less harmful than they would otherwise be. It is hoped that detailed study of the yeast anti-prion systems will facilitate discovery of homologous or analogous mammalian systems active against the many human amyloidoses.

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