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 Table of Contents  
REVIEW
Year : 2021  |  Volume : 16  |  Issue : 3  |  Page : 489-495

Saccharomyces cerevisiae in neuroscience: how unicellular organism helps to better understand prion protein?


Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw, Poland

Date of Submission10-Feb-2020
Date of Decision19-Feb-2020
Date of Acceptance09-Apr-2020
Date of Web Publication22-Sep-2020

Correspondence Address:
Takao Ishikawa
Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw
Poland
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Source of Support: This work was funded by the Polish National Science Centre MINIATURA3, grant No. 501/66 GR-6220 (to TI), Conflict of Interest: None


DOI: 10.4103/1673-5374.293137

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  Abstract 

The baker’s yeast Saccharomyces (S.) cerevisiae is a single-celled eukaryotic model organism widely used in research on life sciences. Being a unicellular organism, S. cerevisiae has some evident limitations in application to neuroscience. However, yeast prions are extensively studied and they are known to share some hallmarks with mammalian prion protein or other amyloidogenic proteins found in the pathogenesis of Alzheimer’s, Parkinson’s, or Huntington’s diseases. Therefore, the yeast S. cerevisiae has been widely used for basic research on aggregation properties of proteins in cellulo and on their propagation. Recently, a yeast-based study revealed that some regions of mammalian prion protein and amyloid β1–42 are capable of induction and propagation of yeast prions. It is one of the examples showing that evolutionarily distant organisms share common mechanisms underlying the structural conversion of prion proteins making yeast cells a useful system for studying mammalian prion protein. S. cerevisiae has also been used to design novel screening systems for anti-prion compounds from chemical libraries. Yeast-based assays are cheap in maintenance and safe for the researcher, making them a very good choice to perform preliminary screening before further characterization in systems engaging mammalian cells infected with prions. In this review, not only classical red/white colony assay but also yeast-based screening assays developed during last year are discussed. Computational analysis and research carried out using yeast prions force us to expect that prions are widely present in nature. Indeed, the last few years brought us several examples indicating that the mammalian prion protein is no more peculiar protein – it seems that a better understanding of prion proteins nature-wide may aid us with the treatment of prion diseases and other amyloid-related medical conditions.

Keywords: amyloid; artificial prion; baker’s yeast; budding yeast; drug screening; fusion protein; neurodegenerative diseases; prion protein; yeast-based assay


How to cite this article:
Ishikawa T. Saccharomyces cerevisiae in neuroscience: how unicellular organism helps to better understand prion protein?. Neural Regen Res 2021;16:489-95

How to cite this URL:
Ishikawa T. Saccharomyces cerevisiae in neuroscience: how unicellular organism helps to better understand prion protein?. Neural Regen Res [serial online] 2021 [cited 2021 Apr 12];16:489-95. Available from: http://www.nrronline.org/text.asp?2021/16/3/489/293137


  Introduction Top


Since research on  Creutzfeldt-Jakob disease More Details, kuru, scrapie, and bovine spongiform encephalopathy–today all known to be caused by proteinaceous infectious particle, or prion–has accelerated half a century ago, various experimental models have been applied to investigate the nature of infectious agent as well as its transmission pathways. Now it is known that prion is the amyloid-type aggregate of prion protein (PrP) encoded by the PRNP gene in mammalian genomes. Mammalian PrP is known to appear in two distinct structural forms– PrPC (cellular, monomeric) and PrPSc (scrapie, with potential for amyloidogenesis). It is well-documented that PrPSc amyloids are the prion particles responsible for the transmission of prion diseases including Creutzfeldt-Jakob disease in humans or scrapie among sheep (Baral et al., 2019).

Amyloidogenesis is triggered by the structural conversion of PrPC into PrPSc. Although misfolded PrPSc is less stable than the native PrPC conformation, its secondary structure is enriched in β-strands, which in turn can form cross-β structure across a number of PrPSc molecules, in this way stabilizing each other. A similar phenomenon is observed for other amyloid-forming proteins that are responsible, in misfolded and aggregated forms, for the development of other neurological disorders like Alzheimer’s, Parkinson’s or Huntington’s diseases (Almeida and Brito, 2020).

As the prion diseases have been identified in mammals, experimental models utilizing mammals have been used to study i.e. inter-species transmission capabilities of these diseases. Not only primates (chimpanzees, cynomolgus macaques, or spider monkeys), but also sheep, cattle, mice, or even nematode (Caenorhabditis elegans) and the fly (Drosophila melanogaster) have been used to bring the scientific community numerous findings regarding prions and diseases caused by them (Brandner and Jaunmuktane, 2017). Recently zebrafish (Danio rerio) has been used as a model organism for studying the role of PrP in neuronal excitability (Kanyo et al., 2020). On the other hand, as numerous examples of iatrogenic transmission of prion diseases (Bonda et al., 2016) or transmission of bovine spongiform encephalopathy to humans causing variant Creutzfeldt-Jakob disease (Houston and Andréoletti, 2019) clearly show, research on mammalian prions in mammalian models is possibly dangerous for the scientific staff dealing with biological materials containing infectious prions.

The baker’s yeast Saccharomyces (S.) cerevisiae is a single-celled eukaryotic model organism widely used in research on life sciences. Various methods for genetic engineering of S. cerevisiae are commonly used, the genome is annotated very well, and the maintenance of yeast cultures is cheap in comparison to mammalian cell cultures or using animals as a model. These features of S. cerevisiae made this unicellular organism one of the favorite model organisms in basic research of molecular biology even serving as a living test tube for neurobiological studies. The advantages of using S. cerevisiae, at the same time, may bring some limitations to the research. Being a unicellular organism, S. cerevisiae obviously cannot serve as the best model for studying issues regarding tissues or organs. However, if basic cellular processes, i.e., protein aggregation in vivo or protein-protein interactions are studied, S. cerevisiae could be a good choice.

Interestingly, the S. cerevisiae Sup35 protein shares the hallmark of the PrP. In monomeric form Sup35p is the essential translation termination factor (Stansfield et al., 1995), whereas in its misfolded form it aggregates to develop amyloid which behaves in the way resembling mammalian PrPSc amyloids–it forms amyloid that prevents it from acting as the translation termination factor (Glover et al., 1997; Paushkin et al., 1997; King and Diaz-Avalos, 2004). It results in [PSI+] phenotype that in certain specific growth conditions gives the advantage for the cells over wild type, or [psi], cells (True and Lindquist, 2000). Both PrPSc and Sup35p amyloids, when transmitted to cells free of amyloids, serve as aggregation foci and give raise to the prion phenotype in recipient cells [Figure 1]. This is the reason why prions are classified as infectious particles.
Figure 1: Common characteristics of mammalian and yeast prion proteins.
Despite unrelated molecular functions of mammalian and yeast prion proteins, they share common hallmarks. The conversion between native and misfolded structures occurs by chance and the latter one is further stabilized by aggregation. For S. cerevisiae it has been shown that amyloid seeds can be provided by other endogenous prions (see below). In the case of the mammalian PrP, it is not still clear, if induction and elongation of amyloids require any other factors. Both mammalian and yeast prions are self-propagating particles – amyloids can force the conversion of native protein into a misfolded form that can be incorporated into the amyloids. They are fragmented once they achieve critically large dimensions. The Hsp104 disaggregase of S. cerevisiae is engaged in the maintenance of this process. Such a mechanism has never been shown in the case of PrPSc amyloids in mammalian cells. Native PrP or Sup35 protein can be converted into a misfolded form and incorporated into amyloids. The dotted arrows indicate hypothetical (for PrP) or non-obligatory (for Sup35p) processes, while solid arrow indicates that Hsp104p is obligatory of the propagation the [PSI+] prion. PrP: Prion protein.


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Although there are no apparent similarities between amino acid sequences, structural features or molecular functions of mammalian PrP and yeast Sup35, there are regions sharing some sequential features that determine their ability for structural conversion. In PrP, the octarepeat domain with PHGGGWGQ sequence has been recognized (residues 60–91), while in Sup35p one can find an oligopeptide repeat region containing five imperfect repeats with PQGGYQQYN as a consensus (residues 41–97). However, there are also fundamental differences between these proteins. Mammalian PrP lacks glutamine/asparagine-rich domain, which is present in yeast Sup35p in the N-terminal domain (residues 1–40) (Liu and Lindquist, 1999). The similarities in the ability for amyloidogenesis and sharing octarepeats, accompanied by the above-mentioned differences, attracted the attention of researchers for studying these proteins to reveal the fundamentals of molecular mechanisms behind the amyloidogenesis phenomenon. It has been shown more than 20 years ago that mammalian PrP expressed in yeast cells produces PrPSc-like conformation in vivo (Ma and Lindquist, 1999). Since then S. cerevisiae has been recognized as one of the models useful in basic research on diseases caused by PrPSc amyloids.


  Search Strategy and Selection Criteria Top


The databases used to select the most relevant papers included in this article were PubMed (www.ncbi.nlm.nih.gov/pubmed/) and Google Scholar (scholar.google.com). Keywords used for the search included: mammalian prion, PRNP gene, prion protein, PrP, yeast prion, Sup35, [PSI+], anti-prion drugs, yeast-based screening system. Articles published in the period from 2000 to 2020 were analyzed, however, the original works published earlier were also considered. Additionally, articles citing papers selected as the result of the search were checked.


  Mammalian Prion Protein in S. cerevisiae Top


Formation of PrPSc in S. cerevisiae cells opened a new chapter in the application of yeast cells in further studies regarding mammalian prions. Here, the most interesting application of yeast-based on the PrP study will be discussed.

One of the applications of S. cerevisiae in research on PrP was the expression of numerous mutant PrP proteins to map the epitope recognized by anti-PrP antibodies. By using yeast surface display method, it was shown that some antibodies fail to recognize PrPSc molecules due to the interaction with α-helix which is converted to β-strand upon structural conversion of whole PrP molecule (Doolan and Colby, 2015). Exact determination of epitopes for anti-prion antibodies is critical for potential immunotherapy of prion diseases. Although there are reports regarding the neurotoxicity of anti-PrP antibodies which cool down enthusiasm for immunotherapy of prion diseases (Reimann et al., 2016), this therapeutic approach is being investigated for Alzheimer’s disease by administrating anti-Aβ and anti-tau oligomers antibodies (Vander Zanden and Chi, 2020).

There are also works bringing up the limitations of S. cerevisiae in studies on mammalian PrP. Jossé et al. (2012) expressed a few versions of the PrP-Sup35 fusion protein in yeast cells to study prion forming capabilities of selected fragments of PrP in cellulo in S. cerevisiae. They found that fragments originating from mammalian PrP not necessarily can ensure stable [PSI+] propagation. For example, when the PrP region known to contribute to PrPC conversion to PrPSc (amino acid residues 93–120) was fused to Sup35p instead of its native N-terminal domain, the fusion protein formed non-amyloid aggregates sensitive to sodium dodecyl sulfate (an anionic surfactant). When this fusion protein contained native Sup35 octarepeats, the aggregate was found to be sodium dodecyl sulfate-resistant, which indicates its amyloid nature, although the determination of molecular mass indicated that it was much smaller in size. Finally, the authors found that several drugs known for their anti-prion activity, including quinacrine, did not cure the prion phenotype of the yeast cells expressing PrP-Sup35 fusion proteins (Jossé et al., 2012). These results clearly show that, although safe and convenient, the yeast model might not be the best one to study mammalian PrP as it is. Rather, as it will be shown in the next section of this review, yeast prions would be the better experimental model to test drug candidates with a wide range of the amyloid targets to cure.

Recently, it has been shown that fusion protein made from Aβ1–42, the most amyloidogenic and pathogenic variant of Aβ associated with Alzheimer’s disease (Näslund et al., 1994), and N-terminal domain of Sup35p promotes the appearance of [PSI+] phenotype in yeasts. The same study covered also fusions of N fragment of Sup35p with fragments of PrP (amino acid residues 90–144, 90–152, or 90–230). Interestingly, results indicate that PrP90–152 is roughly 10- and 100-fold more effective in [PSI+] induction than PrP90–144 or PrP90–230, respectively (Chandramowlishwaran et al., 2018). This shows not only an interesting finding that the peptide fragment accompanied by other fragments of the same protein weakens its capabilities for nucleation, and possibly for structural conversion (PrP90–152 versus PrP90–230), but also that there is a common physical mechanism underlying the amyloid formation by prion and non-PrPs between yeasts and mammals. Despite the conclusions based on the paper by Jossé et al. (2012), the recent paper by Chandramowlishwaran et al. (2018) gives some space for S. cerevisiae to be used as an in cellulo experimental system for studying mammalian PrP and other amyloidogenic proteins.

Limitations of yeast cells are sometimes transformed into an advantage in the design of the experiment. In mammalian cells, some mutants of PrP are known to localize in the membrane, especially those with mutations in the transmembrane segment 1 (TM1) of PrP. About half of TM1 inserted to the endoplasmic reticulum membrane has its N-terminus in the lumen of the endoplasmic reticulum (Ntm orientation), while about 20% exhibits the opposite Ctm orientation. It was shown that increased hydrophobicity of TM1 induces its Ctm orientation (Tipper et al., 2013). In this orientation, differently from the case of Ntm orientation, PrP is secreted from the cell, which in turn has a strong correlation with neuropathology in engineered mice (Hegde et al., 1998).

PrP secretion from mammalian cells requires the translocon-associated protein (TRAP) complex (Fons et al., 2003). The absence of the TRAP complex in S. cerevisiae causes entrapment of PrP molecules in the cell membrane even if their TM1 is inserted in Ctm orientation. By using yeast cells, it has been shown that an increase of charge difference across a transmembrane segment enhances Ctm insertion of PrP and may contribute to its neurotoxicity (Tipper et al., 2013).


  Yeast-Based Anti-Prion Drug Screening Systems Top


Based on the similarities of the basic characteristics of mammalian and yeast prion proteins, S. cerevisiae has been exploited as an initial screening system in search of anti-prion drug candidates. If a particular chemical compound is active against yeast prions (prevents the amyloid formation or has capabilities for its disassembly) it might be active against PrPSc amyloids. This philosophy encouraged researchers to develop yeast strains useful in a preliminary screening of libraries of chemical compounds.

The most widely recognized system is based on [PSI+] strain with ade1-14 or ade2-1 mutation in ADE1 or ADE2 genes, respectively, which namely are premature termination codons (PTCs) in genes essential for adenine biosynthesis (Ishikawa, 2008). Unless [PSI+] is cured (i.e., amyloids are disassembled to monomeric Sup35p molecules) to become [psi], ade1-14 and ade2-1 strains readthrough PTCs and produce active Ade1 and Ade2 enzymes that catalyze cognate biochemical reactions. However, once ade1-14 or ade2-1 cells become [psi], they begin to properly recognize PTCs and fail to produce active enzymes. In low adenine conditions, these cells start to accumulate intermediate products of adenine biosynthesis (phosphoribosylaminoimidazole and/or phosphoribosylaminoimidazole carboxylate), which after oxidization or hydroxylation by cytochrome P450 enzymes form conjugates with reduced glutathione by a non-enzymatic manner. Finally, these molecules are transported to vacuoles to form red pigment, which makes colonies of cured cells red [Figure 2]A.
Figure 2: Yeast-based anti-prion screening systems.
(A) Red/white colony assay utilizing ade1-14 or ade2-1 mutation. The chemical compound with anti-prion activity restores [psi] phenotype, which in ade1-14 or ade2-1 strains leads to the formation of red colonies. It should be noted that this assay may also be performed in liquid cultures. (B) [SWI+] prion-based high throughput assay. The synthesis of uracil is conditioned by the aggregation state of the Swi1 transcription factor. Yeasts grow on ura medium only in the presence of the anti-prion drug when Swi1 is in monomeric, biologically active form. (C) Artificial [LEU2+] prion-based assay. The fragment of SUP35 gene coding for PrD (SUP35NM) was fused with the LEU2 gene under the control of the GAL1-10 promoter. In the presence of galactose, the Sup35NM-Leu2 protein is overexpressed. It forms amyloid which results in reduced leucine synthesis capability (the [LEU2+] phenotype). If the anti-prion drug is present during the pre-culture, the [leu2] phenotype is recovered, thus cells spotted on the leu medium grow with comparative efficiency to the control leu+ medium. The letters X, Y, and Z represent chemical compounds with high, moderate or no anti-prion activity, respectively. NTC: Normal termination codon; OD600: optical density at 600 nm; prFLO1: promoter of the FLO1 gene; prGAL1-10; promoter of GAL1 and GAL10 genes; PTC: premature termination codon.


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Applications of this test in search of anti-prion drug candidates will be discussed below, but it is worth to mention here that the requirement of a sufficient level of reduced glutathione to develop red pigment has been used for another amyloid-related yeast-based assay to evaluate oxidative stress caused by overexpression of amyloidogenic proteins. The appearance of white colonies upon overexpression of these proteins and reversions to red ones after shutting off the transcription confirmed that amyloids, like Aβ1–42, expressed in S. cerevisiae generate oxidative stress (Bharathi et al., 2016). Interestingly, exposure of the yeast cells to 2.0 GHz radiofrequency electromagnetic field, the same frequency as used in the 4th generation long-term evolution and the 5th generation wireless technologies for digital cellular networks, caused the de novo formation of yeast prions, as well as resulted in the elevated level of reactive oxygen species and expression of superoxide dismutase and catalase (Lian et al., 2018). These yeast-based findings might be a preceding result, which should be investigated also concerning amyloids found in mammalian neurons.

Screening of anti-prion drug candidates utilizing ade1-14 or ade2-1 strains are performed as follows: ade1-14 [PSI+] or ade2-1 [PSI+] strain is spread on the surface of the solid growth medium, small disks made from filter paper are placed on the surface and chemical compounds to be assessed are spotted on the disks. After a few days of growth, the surface of the growth medium is covered with numerous white colonies, whereas around the disks containing active drugs against [PSI+] prion colonies are red [Figure 2]A. In case the drug candidate is lethal for yeasts, there is a clear zone on the surface of the growth medium around the disk.

This screening method has been utilized for decades to reveal several anti-prion drug candidates. Doxorubicin (Tagliavini et al., 1997), quinacrine (Doh-Ura et al., 2000; Korth et al., 2001), kastellpaolitines, 6-aminophenanthridine (Bach et al., 2003), pentosan polysulfate (Rainov et al., 2007), guanabenz acetate (Tribouillard-Tanvier et al., 2008), imiquimod (Oumata et al., 2013), and bromotyrosine derivatives (Jennings et al., 2018) have been positively evaluated by red/white colony assay.

Some of these compounds have been further evaluated by different experimental approaches. On the prion-infected mouse ScN2a neuroblastoma model, it has been shown that pentosan polysulfate directly binds to PrPC and at the same time decreases PrPSc level, although its mechanism has not been determined (Yamasaki et al., 2014).

Besides mammalian neurons infected by prions widely used as a model system, one of the emerging anti-prion assays is a shaking-induced conversion of PrP. Shaking of the solution containing recombinant PrP boosts its aggregation, which can be easily and quantitatively evaluated by resolution enhanced native acidic gel electrophoresis (Ladner-Keay et al., 2018). This study revealed that quinacrine binds specifically to PrPC and prevents this protein from forming amyloid fibrils (Ladner-Keay et al., 2018). The shaking-induced conversion method shares some principles with a real-time quaking-induced conversion method described earlier (Atarashi et al., 2011). Differently from the shaking-induced conversion method, real-time quaking-induced conversion is quantified by the measurement of fluorescence emitted due to specific interaction of thioflavin T with PrPSc amyloids (Green, 2019).

It should be stressed that the red/white colony assay has been further improved for high-throughput studies. Jennings and colleagues recently showed that butenolides and diphenylpropanones isolated from ascidian tunicate Polycarpa procera have anti-prion activity by the liquid version of red/white colony assay. They reported that the assay was performed in 96-well or 384-well plates containing yeast mini-cultures supplemented with investigated chemical compounds. Next, plates were photographed and red color intensity was measured by image analysis software or quantified by measuring fluorescence (excitation 544 nm/emission 620 nm) on a microplate fluorimeter (Jennings et al., 2019).

A similar approach but the different mechanism has been employed in recently published high-throughput anti-prion activity assay. Briefly, the novel assay is all about the ability of yeast cells to grow on liquid medium lacking uracil–when amyloid fibrils are present in the cytoplasm, cells are not able to grow on ura medium, while when cured they produce uracil by themselves and grow even in the absence of this nitrogen base. The authors designed the yeast strain in which a coding sequence of the FLO1 gene was replaced by the URA3 gene which restores the cell’s ability to synthesize uracil. However, the expression of Ura3 protein was controlled by the promoter of the FLO1 gene, which in turn is controlled by the Swi1 transcription factor known to form amyloids in S. cerevisiae cells. Therefore, aggregation of Swi1 known as [SWI+] phenotype prevented yeasts from growing on ura medium, and curing them to [swi] restored their growth. Measuring OD600 of growth media on multi-well plates containing different anti-prion drug candidates was sufficient to evaluate the activity of the chemical compound (Du et al. 2019) [Figure 2]B. Among anti-prion compounds identified by this assay, phloretin and pilocarpine have been never reported as active against yeast prions. Interestingly, phloretin was also reported to exhibit a modulatory role in the activity of Aβ25–35 in inducing sporadic Alzheimer’s disease in the rat (Ghumatkar et al., 2019).

The above-mentioned Swi1p is a good example to show that yeast PrPs are modular. It has been demonstrated that replacement of N-terminal residues 1–40 of Sup35p with residues 1–38 from Swi1p maintained an ability of engineered Sup35p to form prion aggregates and to exhibit [PSI+] phenotype. The modular nature of yeast prions has been successfully implemented in another yeast-based screening system. Recently, we created novel fusion protein Sup35NM-Leu2p consist of amino acid residues 1–123 from Sup35 (Sup35NM, designated also as prion-forming domain; PrD) and Leu2p (β-isopropylmalate dehydrogenase) taking part in leucine synthesis pathway in yeast cells. By expressing the fusion protein in a leu2Δ host strain, the aggregation status of Sup35NM-Leu2 protein solely determines the ability of the yeast cells to synthesize leucine or not. Therefore, in this assay anti-prion drug candidates are added to the liquid medium while yeasts are growing in leu+ medium, and then they are spotted on the leu plates to evaluate the status of Sup35NM-Leu2p, which reflects an anti-prion activity of the drug being evaluated (Ishikawa and Lisiecki, 2020) [Figure 2]C. The development of the liquid-medium version of this assay, similar to the [SWI+]-based one, seems to be possible and currently, it is under investigation (unpublished data).

Interestingly, a cholinesterase inhibitor 6-chlorotacrine which is currently tested as a drug against Alzheimer’s disease (Misik et al., 2018; Kaniakova et al., 2019) has been positively evaluated as active against yeast [PSI+] prion in red/white colony assay (Ishikawa and Lisiecki, 2020). However, when the same compound was assessed using a novel screening-system employing artificial [LEU2+], it did not support the former result, although other anti-prion compounds like tacrine, 6-aminophenantridine, or guanabenz acetate retained their anti-prion activity against [LEU2+] prion (Ishikawa and Lisiecki, 2020). It indicates that even in a preliminary screening of libraries of chemical compounds performed on yeast-based systems, false-positive or false-negative results may arise. Current availability of at least three different yeast-based screening assays ([PSI+] red/white assay, [SWI+] growth assay, and [LEU2+] growth assay) makes it possible to cross-check preliminary results on cheap and safe yeast-based assays, to proceed to mammalian cell-based tests with only well-evaluated chemical compounds.


  Prions are More Common Than Once Thought to Be? Top


For a long time, the [PSI+] prion was the representative yeast prion together with other few well-studied examples including [URE3] and [PIN+]. It seemed, more or less, like yeast PrPs are rather uncommon and awkward protein examples just as PrP in mammalian cells was. This landscape radically changed in 2009 when a breakthrough paper by Alberti et al. (2009) was published. By analyzing the S. cerevisiae genome, they found about 200 putative PrDs and confirmed 19 of these to form prion in vivo (Alberti et al., 2009). Among newly discovered prions, there was [MOT3+], which is an aggregated Mot3 transcriptional regulator. It can be easily imagined how pleiotropic the effects of such aggregation and disaggregation might be. From this moment, many yeast prions have been discovered. Among biologically interesting examples the [GAR+] prion should be mentioned. This prion phenotype cancels catabolic repression and facilitates yeast cells to catabolize non-fermentative carbon sources even in the presence of glucose (Jarosz et al., 2014). Follow-up studies revealed that wild-type yeast cells can become [GAR+] under the influence of lactic acid secreted by bacterial cells (Garcia et al., 2016). One possible explanation of this phenomenon is the advantage for bacteria residing in the same ecological niche as yeasts, because reduced production of ethanol by yeast cells may favor bacterial growth.

The [SMAUG+] prion is the freshest yeast prion reported to date (Itakura et al., 2020). This prion phenotype, which is the result of Vts1 protein aggregation, has a strong repressive effect on the production of proteins triggering meiosis, or the formation of spores. Based on the aggregation status of Vts1p, yeast cells enter mitotic reproduction performed in nutrient-rich conditions, while during starvation they rather form stress-resistant spores. This decision is made by epigenetic, protein-based switch – the [SMAUG+] prion [Table 1].
Table 1: Prion proteins and phenotypes identified in S. cerevisiae

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The year 2020 may be another breakthrough in studies on yeast prions. The [SMAUG+] prion, or aggregated Vts1p, appears to be a non-amyloid, self-assembling, gel-like particle that hyperactivates its component (Chakravarty et al., 2020). The Vts1 protein binds specific hairpin structures within RNA, thus triggering their degradation, specifically transcripts encoding meiotic proteins. The traditional way of understanding prions was to expect that proteins trapped in amyloids have no or limited biological activity. Recent reports regarding [SMAUG+] prion revolutionizes our view on the nature of prions.

These examples just strengthen the doubt – is it possible that only yeasts have such a wide variety of prion proteins? Computational analyses bring some insights into this issue. PrionHome is a database of prionogenic sequences (Harbi et al., 2012; online database seems to be discontinued as of April 2020). It predicts prionogenic sequence either by glutamine/asparagine-richness or by using the Hidden Markov Model algorithm successfully implemented by Alberti et al. (2009). In the initial version of PrionHome, there were 20 different mammalian prionogenic sequences registered with more than 400 orthologs of these proteins (Harbi et al., 2012). The other group maintains the PrionScan database which employs the probabilistic model also based on the algorithm by Alberti et al. (2009), which at the time of its publication counted about 650 prionogenic sequences in mammalian proteomes. The PrionScan algorithm predicted also 5460 bacterial, 15,549 invertebrate, 934 plant, and 226 viral prionogenic sequences (Espinosa Angarica et al., 2014). Many observations confirm these predictions – the Rho protein governing the transcription process in Clostridium botulinum (Yuan and Hochschild, 2017), the CPEB protein in sea slug Aplysia californica (Heinrich and Lindquist, 2011) or CPEB Orb2 in Drosophila melanogaster (Majumdar et al., 2012) engaged in the persistence of memory, and Luminidependens protein controlling the flowering in Arabidopsis thaliana (Chakrabortee et al., 2016) have been demonstrated to display prion properties. To complete this landscape, the discovery of viral protein with prion properties has been looked forward to for a long time. Finally, last year such protein has been found–LEF-10 transcription factor from baculovirus not only has prion properties but also is capable to replace PrD of yeast Sup35 protein (Nan et al., 2019).

These discoveries show that prion and prion-like proteins are not only expected to exist in the wide range of organisms in nature, but they really do exist and probably are waiting to be uncovered. A recent report shows that at least some of the potential prion and prion-like proteins in mammals have been difficult to identify due to the alternative splicing events (Cascarina and Ross, 2020). The next few years will likely deliver a completely different view of prion proteins. Now it became clear that mammalian prion protein is not the only prion protein in multicellular eukaryotes.

Acknowledgments: The author thanks the reviewers for their constructive comments that greatly contributed to improving the final version of the review.

Author contributions: The author completed the manuscript independently and approved the final manuscript.

Conflicts of interest: The author declares no conflicts of interest.

Financial support: This work was funded by the Polish National Science Centre MINIATURA3, grant No. 501/66 GR-6220 (to TI).

Copyright license agreement: The Copyright License Agreement has been signed by the author before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Funding: This work was funded by the Polish National Science Centre MINIATURA3, grant No. 501/66 GR-6220 (to TI).

 
  References Top

1.
Alberti S, Halfmann R, King O, Kapila A, Lindquist S (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137:146-158.  Back to cited text no. 1
    
2.
Almeida Z, Brito R (2020) Structure and aggregation mechanisms in amyloids. Molecules 25:E1195.  Back to cited text no. 2
    
3.
Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D, Matsubara T, Nakagaki T, Yamanaka H, Shirabe S, Yamada M, Mizusawa H, Kitamoto T, Klug G, McGlade A, Collins SJ, Nishida N (2011) Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 17:175-178.  Back to cited text no. 3
    
4.
Bach S, Talarek N, Andrieu T, Vierfond JM, Mettey Y, Galons H, Dormont D, Meijer L, Cullin C, Blondel M (2003) Isolation of drugs active against mammalian prions using a yeast-based screening assay. Nat Biotechnol 21:1075-1081.  Back to cited text no. 4
    
5.
Baral PK, Yin J, Aguzzi A, James MNG (2019) Transition of the prion protein from a structured cellular form (PrPC) to the infectious scrapie agent (PrPSc). Protein Sci 28:2055-2063.  Back to cited text no. 5
    
6.
Bharathi V, Girdhar A, Prasad A, Verma M, Taneja V, Patel BK (2016) Use of ade1 and ade2 mutations for development of a versatile red/white colour assay of amyloid-induced oxidative stress in Saccharomyces cerevisiae. Yeast 33:607-620.  Back to cited text no. 6
    
7.
Bonda DJ, Manjila S, Mehndiratta P, Khan F, Miller BR, Onwuzulike K, Puoti G, Cohen ML, Schonberger LB, Cali I (2016) Human prion diseases: surgical lessons learned from iatrogenic prion transmission. Neurosurg Focus 41:E10.  Back to cited text no. 7
    
8.
Brandner S, Jaunmuktane Z (2017) Prion disease: experimental models and reality. Acta Neuropathol 133:197-222.  Back to cited text no. 8
    
9.
Brown JC, Lindquist S (2009) A heritable switch in carbon source utilization driven by an unusual yeast prion. Genes Dev 23:2320-2332.  Back to cited text no. 9
    
10.
Cascarina SM, Ross ED (2020) Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes. BMC Genomics 21:23.  Back to cited text no. 10
    
11.
Chakrabortee S, Kayatekin C, Newby GA, Mendillo ML, Lancaster A, Lindquist S (2016) Luminidependens (LD) is an Arabidopsis protein with prion behavior. Proc Natl Acad Sci U S A 113:6065-6070.  Back to cited text no. 11
    
12.
Chakravarty AK, Smejkal T, Itakura AK, Garcia DM, Jarosz DF (2020) A non-amyloid prion particle that activates a heritable gene expression program. Mol Cell 77:251-265.e9.  Back to cited text no. 12
    
13.
Chandramowlishwaran P, Sun M, Casey KL, Romanyuk AV, Grizel AV, Sopova JV, Rubel AA, Nussbaum-Krammer C, Vorberg IM, Chernoff YO (2018) Mammalian amyloidogenic proteins promote prion nucleation in yeast. J Biol Chem 293:3436-3450.  Back to cited text no. 13
    
14.
Chen LJ, Sawyer EB, Perrett S (2011) The yeast prion protein Ure2: insights into the mechanism of amyloid formation. Biochem Soc Trans 39:1359-1364.  Back to cited text no. 14
    
15.
Chernova TA, Wilkinson KD, Chernoff YO (2014) Physiological and environmental control of yeast prions. FEMS Microbiol Rev 38:326-344.  Back to cited text no. 15
    
16.
Chernova TA, Kiktev DA, Romanyuk AV, Shanks JR, Laur O, Ali M, Ghosh A, Kim D, Yang Z, Mang M, Chernoff YO, Wilkinson KD (2017) Yeast short-lived actin-associated protein forms a metastable prion in response to thermal stress. Cell Rep 18:751-761.  Back to cited text no. 16
    
17.
Cox BS (1965) [PSI], a cytoplasmic suppressor of super-suppressors in yeast. Heredity 20:505-521.  Back to cited text no. 17
    
18.
Cox B, Tuite M (2017) The life of [PSI]. Curr Genet 64:1-8.  Back to cited text no. 18
    
19.
Crow ET, Li L (2011) Newly identified prions in budding yeast, and their possible functions. Semin Cell Dev Biol 22:452-459.  Back to cited text no. 19
    
20.
Derkatch IL, Bradley ME, Zhou P, Chernoff YO, Liebman SW (1997) Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae. Genetics 147:507-519.  Back to cited text no. 20
    
21.
Derkatch IL, Bradley ME, Hong JY, Liebman SW (2001) Prions affect the appearance of other prions: the story of [PIN+]. Cell 106:171-182.  Back to cited text no. 21
    
22.
Doh-Ura K, Iwaki T, Caughey B (2000) Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol 74:4894-4897.  Back to cited text no. 22
    
23.
Doolan KM, Colby DW (2015) Conformation-dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing. J Mol Biol 427:328-340.  Back to cited text no. 23
    
24.
Du Z, Park KW, Yu H, Fan Q, Li L (2008) Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae. Nat Genet 40:460-465.  Back to cited text no. 24
    
25.
Du Z, Valtierra S, Cardona LR, Dunne SF, Luan CH, Li L (2019) Identifying anti-prion chemical compounds using a newly established yeast high-throughput screening system. Cell Chem Biol 26:1664-1680.e4.  Back to cited text no. 25
    
26.
Espinosa Angarica V, Angulo A, Giner A, Losilla G, Ventura S, Sancho J (2014) PrionScan: an online database of predicted prion domains in complete proteomes. BMC Genomics 15:102.  Back to cited text no. 26
    
27.
Fons RD, Bogert BA, Hegde RS (2003) Substrate-specific function of the translocon-associated protein complex during translocation across the ER membrane. J Cell Biol 160:529-539.  Back to cited text no. 27
    
28.
Garcia DM, Dietrich D, Clardy J, Jarosz DF (2016) A common bacterial metabolite elicits prion-based bypass of glucose repression. Elife 5:e17978.  Back to cited text no. 28
    
29.
Ghumatkar PJ, Patil SP, Peshattiwar V, Vijaykumar T, Dighe V, Vanage G, Sathaye S (2019) The modulatory role of phloretin in Aβ25-35 induced sporadic Alzheimer’s disease in rat model. Naunyn Schmiedebergs Arch Pharmacol 392:327-339.  Back to cited text no. 29
    
30.
Glover JR, Kowal AS, Schirmer EC, Patino MM, Liu JJ, Lindquist S (1997) Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae. Cell 89:811-819.  Back to cited text no. 30
    
31.
Goncharoff DK, Du Z, Li L (2018) A brief overview of the Swi1 prion – [SWI+]. FEMS Yeast Res doi: 10.1093/femsyr/foy061.  Back to cited text no. 31
    
32.
Green AJE (2019) RT-QuIC: a new test for sporadic CJD. Practical Neurology 19:49-55.  Back to cited text no. 32
    
33.
Halfmann R, Wright JR, Alberti S, Lindquist S, Rexach M (2012) Prion formation by a yeast GLFG nucleoporin. Prion 6:391-399.  Back to cited text no. 33
    
34.
Harbi D, Parthiban M, Gendoo DM, Ehsani S, Kumar M, Schmitt-Ulms G, Sowdhamini R, Harrison PM (2012) PrionHome: a database of prions and other sequences relevant to prion phenomena. PLoS One 7:e31785.  Back to cited text no. 34
    
35.
Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond SJ, Prusiner SB, Lingappa VR (1998) A transmembrane form of the prion protein in neurodegenerative disease. Science 279:827-834.  Back to cited text no. 35
    
36.
Heinrich SU, Lindquist S (2011) Protein-only mechanism induces self-perpetuating changes in the activity of neuronal Aplysia cytoplasmic polyadenylation element binding protein (CPEB). Proc Natl Acad Sci U S A 108:2999-3004.  Back to cited text no. 36
    
37.
Houston F, Andréoletti O (2019) Animal prion diseases: the risks to human health. Brain Pathol 29:248-262.  Back to cited text no. 37
    
38.
Ishikawa T (2008) Recent advances of research on the [PSI+] prion in Saccharomyces cerevisiae. Mycoscience 49:221-228.  Back to cited text no. 38
    
39.
Ishikawa T, Lisiecki K (2020) Anti-prion drug screening system in Saccharomyces cerevisiae based on an artificial [LEU2+] prion, Fungal Genet Biol 134:103280  Back to cited text no. 39
    
40.
Itakura AK, Chakravarty AK, Jakobson CM, Jarosz DF (2020) Widespread prion-based control of growth and differentiation strategies in Saccharomyces cerevisiae. Mol Cell 77:266-278.e6.  Back to cited text no. 40
    
41.
Jarosz DF, Lancaster AK, Brown JCS, Lindquist S (2014) An evolutionarily conserved prion-like element converts wild fungi from metabolic specialists to generalists. Cell 158:1072-1082.  Back to cited text no. 41
    
42.
Jennings LK, Ahmed I, Munn AL, Carroll AR (2018) Yeast-based screening of natural product extracts results in the identification of prion inhibitors from a marine sponge. Prion 12:234-244.  Back to cited text no. 42
    
43.
Jennings LK, Robertson LP, Rudolph KE, Munn AL, Carroll AR (2019) Anti-prion butenolides and diphenylpropanones from the Australian Ascidian Polycarpa procera. J Nat Prod 82:2620-2626.  Back to cited text no. 43
    
44.
Jossé L, Marchante R, Zenthon J, von der Haar T, Tuite MF (2012) Probing the role of structural features of mouse PrP in yeast by expression as Sup35-PrP fusions. Prion 6:201-210.  Back to cited text no. 44
    
45.
Kaniakova M, Nepovimova E, Kleteckova L, Skrenkova K, Holubova K, Chrienova Z, Hepnarova V, Kucera T, Kobrlova T, Vales K, Korabecny J, Soukup O, Horak M (2019) Combination of memantine and 6-chlorotacrine as novel multi-target compound against Alzheimer’s disease. Curr Alzheimer Res 16:821-833.  Back to cited text no. 45
    
46.
Kanyo R, Leighton PLA, Neil GJ, Locskai LF, Allison WT (2020) Amyloid-β precursor protein mutant zebrafish exhibit seizure susceptibility that depends on prion protein. Exp Neurol 328:113283.  Back to cited text no. 46
    
47.
King CY, Diaz-Avalos R (2004) Protein-only transmission of three yeast prion strains. Nature 428:319-323.  Back to cited text no. 47
    
48.
Korth C, May BC, Cohen FE, Prusiner SB (2001) Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A 98:9836-9841.  Back to cited text no. 48
    
49.
Lacroute F (1971) Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast. J Bacteriol 106:519-522.  Back to cited text no. 49
    
50.
Ladner-Keay CL, Ross L, Perez-Pineiro R, Zhang L, Bjorndahl TC, Cashman N, Wishart DS (2018) A simple in vitro assay for assessing the efficacy, mechanisms and kinetics of anti-prion fibril compounds. Prion 12:280-300.  Back to cited text no. 50
    
51.
Lian HY, Lin KW, Yang C, Cai P (2018) Generation and propagation of yeast prion [URE3] are elevated under electromagnetic field. Cell Stress Chaperones 23:581-594.  Back to cited text no. 51
    
52.
Liu JJ, Lindquist S (1999) Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast. Nature 400:573-576.  Back to cited text no. 52
    
53.
Ma J, Lindquist S (1999) De novo generation of a PrPSc-like conformation in living cells. Nat Cell Biol 1:358-361.  Back to cited text no. 53
    
54.
Majumdar A, Cesario WC, White-Grindley E, Jiang H, Ren F, Khan MR, Li L, Choi EM, Kannan K, Guo F, Unruh J, Slaughter B, Si K (2012) Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148:515-529.  Back to cited text no. 54
    
55.
Manjrekar J, Shah H (2020) Protein-based inheritance. Semin Cell Dev Biol 97:138-155.  Back to cited text no. 55
    
56.
Misik J, Nepovimova E, Pejchal J, Kassa J, Korabecny J, Soukup O (2018) Cholinesterase inhibitor 6-chlorotacrine – in vivo toxicological profile and behavioural effects. Curr Alzheimer Res 15:552-560.  Back to cited text no. 56
    
57.
Nan H, Chen H, Tuite MF, Xu X (2019) A viral expression factor behaves as a prion. Nat Commun 10:359.  Back to cited text no. 57
    
58.
Na?slund J, Schierhorn A, Hellman U, Lannfelt L, Roses AD, Tjernberg LO, Silberring J, Gandy SE, Winblad B, Greengard P (1994) Relative abundance of Alzheimer Aβ amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci U S A 91:8378-8382.  Back to cited text no. 58
    
59.
Nizhnikov AA, Magomedova ZM, Rubel AA, Kondrashkina AM, Inge-Vechtomov SG, Galkin AP (2012) [NSI+] determinant has a pleiotropic phenotypic manifestation that is modulated by SUP35, SUP45, and VTS1 genes. Curr Genet 58:35-47.  Back to cited text no. 59
    
60.
Nizhnikov AA, Ryzhova TA, Volkov KV, Zadorsky SP, Sopova JV, Inge-Vechtomov SG, Galkin AP (2016) Interaction of prions causes heritable traits in Saccharomyces cerevisiae. PLoS Genet 12:e1006504.  Back to cited text no. 60
    
61.
Oumata N, Nguyen PH, Beringue V, Soubigou F, Pang Y, Desban N, Massacrier C, Morel Y, Paturel C, Contesse MA, Bouaziz S, Sanyal S, Galons H, Blondel M, Voisset C (2013) The toll-like receptor agonist imiquimod is active against prions. PLoS One 8:e72112.  Back to cited text no. 61
    
62.
Parfenova I, Barral Y (2020) Yeast sporulation and [SMAUG+] prion: faster is not always better. Mol Cell 77:203-204.  Back to cited text no. 62
    
63.
Patel BK, Gavin-Smyth J, Liebman SW (2009) The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion. Nat Cell Biol 11:344-349.  Back to cited text no. 63
    
64.
Paushkin SV, Kushnirov VV, Smirnov VN, Ter-Avanesyan MD (1997) In vitro propagation of the prion-like state of yeast Sup35 protein. Science 277:381-383.  Back to cited text no. 64
    
65.
Rainov NG, Tsuboi Y, Krolak-Salmon P, Vighetto A, Doh-Ura K (2007) Experimental treatments for human transmissible spongiform encephalopathies: is there a role for pentosan polysulfate? Expert Opin Biol Ther 7:713-726.  Back to cited text no. 65
    
66.
Reimann RR, Sonati T, Hornemann S, Herrmann US, Arand M, Hawke S, Aguzzi A (2016) Differential toxicity of antibodies to the prion protein. PLoS Pathog 12:e1005401.  Back to cited text no. 66
    
67.
Roberts BT, Wickner RB (2003) Heritable activity: a prion that propagates by covalent autoactivation. Genes Dev 17:2083-2087.  Back to cited text no. 67
    
68.
Roberts BT, Wickner RB (2004) A new kind of prion: a modified protein necessary for its own modification. Cell Cycle 3:100-103.  Back to cited text no. 68
    
69.
Rogoza TM, Viktorovskaia OV, Rodionova SA, Ivanov MS, Volkov KV, Mironova LN (2009) Search for the genes critical for propagation of the prion-like antisuppressor determinant [ISP+] in yeast using insertion library. Mol Biol (Mosk) 43:392-399.  Back to cited text no. 69
    
70.
Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, Volkov K, Mironova L (2010) Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1. Proc Natl Acad Sci U S A 107:10573-10577.  Back to cited text no. 70
    
71.
Saifitdinova AF, Nizhnikov AA, Lada AG, Rubel AA, Magomedova ZM, Ignatova VV, Inge-Vechtomov SG, Galkin AP (2010) [NSI+]: a novel non-Mendelian nonsense suppressor determinant in Saccharomyces cerevisiae. Curr Genet 56:467-478.  Back to cited text no. 71
    
72.
Serio TR (2018) [PIN+]ing down the mechanism of prion appearance. FEMS Yeast Res doi: 10.1093/femsyr/foy026.  Back to cited text no. 72
    
73.
Stansfield I, Jones KM, Kushnirov VV, Dagkesamanskaya AR, Poznyakovski AI, Paushkin SV, Nierras CR, Cox BS, Ter-Avanesyan MD, Tuite MF (1995) The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. EMBO J 14:4365-4373.  Back to cited text no. 73
    
74.
Suzuki G, Shimazu N, Tanaka M (2012) A yeast prion, Mod5, promotes acquired drug resistance and cell survival under environmental stress. Science 336:355-359.  Back to cited text no. 74
    
75.
Suzuki G, Tanaka M (2013) Expanding the yeast prion world: active prion conversion of non-glutamine/asparagine-rich Mod5 for cell survival. Prion 7:109-113.  Back to cited text no. 75
    
76.
Tagliavini F, McArthur RA, Canciani B, Giaccone G, Porro M, Bugiani M, Lievens PM, Bugiani O, Peri E, Dall’Ara P, Rocchi M, Poli G, Forloni G, Bandiera T, Varasi M, Suarato A, Cassutti P, Cervini MA, Lansen J, Salmona M, et al. (1997) Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science 276:1119-1122.  Back to cited text no. 76
    
77.
Tipper D, Martinez-Vilchez I, Markgren L, Kagalwala DZ (2013) Mammalian prion protein expression in yeast; a model for transmembrane insertion. Prion 7:477-487.  Back to cited text no. 77
    
78.
True HL, Lindquist SL (2000) A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407:477-483.  Back to cited text no. 78
    
79.
Tuite MF (2016) An acid tale of prion formation. Elife 5:e22256.  Back to cited text no. 79
    
80.
Tribouillard-Tanvier D, Béringue V, Desban N, Gug F, Bach S, Voisset C, Galons H, Laude H, Vilette D, Blondel M (2008) Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions. PLoS One 3:e1981.  Back to cited text no. 80
    
81.
Vander Zanden CM, Chi EY (2020) Passive immunotherapies targeting amyloid beta and tau oligomers in Alzheimer’s disease. J Pharm Sci 109:68-73.  Back to cited text no. 81
    
82.
Yamasaki T, Suzuki A, Hasebe R, Horiuchi M (2014) Comparison of the anti-prion mechanism of four different anti-prion compounds, anti-PrP monoclonal antibody 44B1, pentosan polysulfate, chlorpromazine, and U18666A, in prion-infected mouse neuroblastoma cells. PLoS One 9:e106516.  Back to cited text no. 82
    
83.
Yuan AH, Hochschild A (2017) A bacterial global regulator forms a prion. Science 355:198-201.  Back to cited text no. 83
    

C-Editors: Zhao M, Li JY; T-Editor: Jia Y


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International Journal of Molecular Sciences. 2020; 22(1): 90
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