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Special Issue "Yeast Killer Toxins"

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (30 September 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Manfred J. Schmitt

Molecular and Cell Biology, Department of Biosciences and Center of Human and Molecular Biology, Saarland University, D-66123 Saarbrücken, Germany
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Special Issue Information

Dear Colleagues,

The initial discovery of killer toxin-secreting strains in the yeast Saccharomyces cerevisiae and its phenotypic association with the presence of cytoplasmic persisting double-stranded (ds)RNA viruses marked the beginning of intense research in the fields of killer toxin biology and yeast virology in the mid 1960s and early 1970s. Shortly thereafter it became evident that killer toxin secreting yeasts can be frequently found within the fungal kingdom, and that even some killer toxins bear a pronounced antimycotic potential by effectively killing human and plant pathogenic yeasts and fungi. While the genetic basis of a killer phenotype in yeast is strikingly diverse, ranging from killer toxins encoded by chromosomal genes, cytoplasmic virus-like elements (VLE), or encapsidated dsRNA viruses, in vivo toxicity is usually initiated in a receptor-mediated two-step process after which the toxins either enter cells by endocytosis to reach the final molecular target(s) or disrupt plasma membrane or cell wall integrity and function. Since the vast majority of killer toxins selectively kill yeasts and fungi, toxin-specific immunity or antitoxin components have coevolved to prevent killer yeasts from suicide.

After more than 50 years of research much has been learned about eukaryotic cell biology and virus/host interactions by dissecting processes such as killer toxin precursor processing, toxin maturation and secretion, and mode of cell killing. Such studies fostered our understanding and current view of processes that are likewise fundamental to cell biology and to various human diseases, including mechanisms of host cell intoxication, intracellular toxin transport and translocation from endomembranes, protein ubiquitylation and proteasomal degradation, tRNA anticodon cleavage, and even apoptotic cell death. Research in this field has proven of general importance in understanding eukaryotic cell biology and, in addition, becomes increasingly interesting for biomedical and biotechnological applications. This Special Issue will cover some of these aspects in this still timely and fascinating field of “Yeast Killer Toxins”.

Prof. Dr. Manfred J. Schmitt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • killer yeasts
  • protein toxins
  • toxin immunity
  • cell surface receptors
  • intracellular trafficking
  • endomembrane transport
  • pore formation
  • anticodon ribonuclease
  • virus/host cell interactions
  • cell cycle control and apoptosis
  • antimycotics

Published Papers (9 papers)

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Research

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Open AccessArticle
Candidacidal Activity of a Novel Killer Toxin from Wickerhamomyces anomalus against Fluconazole-Susceptible and -Resistant Strains
Received: 1 December 2017 / Revised: 30 January 2018 / Accepted: 1 February 2018 / Published: 3 February 2018
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Abstract
The isolation and characterization from the sand fly Phlebotomus perniciosus of a Wickerhamomyces anomalus yeast strain (Wa1F1) displaying the killer phenotype was recently reported. In the present work, the killer toxin (KT) produced by Wa1F1 was purified and characterized, and [...] Read more.
The isolation and characterization from the sand fly Phlebotomus perniciosus of a Wickerhamomyces anomalus yeast strain (Wa1F1) displaying the killer phenotype was recently reported. In the present work, the killer toxin (KT) produced by Wa1F1 was purified and characterized, and its antimicrobial activity in vitro was investigated against fluconazole- susceptible and -resistant clinical isolates and laboratory strains of Candida albicans and C. glabrata displaying known mutations. Wa1F1-KT showed a differential killing ability against different mutant strains of the same species. The results may be useful for the design of therapeutic molecules based on Wa1F1-KT and the study of yeast resistance mechanisms. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Open AccessFeature PaperArticle
Expression of K1 Toxin Derivatives in Saccharomyces cerevisiae Mimics Treatment with Exogenous Toxin and Provides a Useful Tool for Elucidating K1 Mechanisms of Action and Immunity
Toxins 2017, 9(11), 345; https://doi.org/10.3390/toxins9110345
Received: 28 September 2017 / Revised: 10 October 2017 / Accepted: 25 October 2017 / Published: 27 October 2017
Cited by 2 | PDF Full-text (1453 KB) | HTML Full-text | XML Full-text
Abstract
Killer toxin K1 is a heterodimeric protein toxin secreted by Saccharomyces cerevisiae strains infected with the M1 double-stranded RNA ‘killer’ virus. After binding to a primary receptor at the level of the cell wall, K1 interacts with its secondary plasma membrane receptor Kre1p, [...] Read more.
Killer toxin K1 is a heterodimeric protein toxin secreted by Saccharomyces cerevisiae strains infected with the M1 double-stranded RNA ‘killer’ virus. After binding to a primary receptor at the level of the cell wall, K1 interacts with its secondary plasma membrane receptor Kre1p, eventually leading to an ionophoric disruption of membrane function. Although it has been under investigation for decades, neither the particular mechanisms leading to toxicity nor those leading to immunity have been elucidated. In this study, we constructed derivatives of the K1α subunit and expressed them in sensitive yeast cells. We show that these derivatives are able to mimic the action of externally applied K1 toxin in terms of growth inhibition and pore formation within the membrane, leading to a suicidal phenotype that could be abolished by co-expression of the toxin precursor, confirming a mechanistic similarity of external and internal toxin action. The derivatives were successfully used to investigate a null mutant completely resistant to externally applied toxin. They provide a valuable tool for the identification of so far unknown gene products involved in K1 toxin action and/or immunity. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Open AccessArticle
Variation and Distribution of L-A Helper Totiviruses in Saccharomyces sensu stricto Yeasts Producing Different Killer Toxins
Toxins 2017, 9(10), 313; https://doi.org/10.3390/toxins9100313
Received: 14 September 2017 / Revised: 2 October 2017 / Accepted: 6 October 2017 / Published: 11 October 2017
Cited by 3 | PDF Full-text (3207 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Yeasts within the Saccharomyces sensu stricto cluster can produce different killer toxins. Each toxin is encoded by a medium size (1.5–2.4 Kb) M dsRNA virus, maintained by a larger helper virus generally called L-A (4.6 Kb). Different types of L-A are found associated [...] Read more.
Yeasts within the Saccharomyces sensu stricto cluster can produce different killer toxins. Each toxin is encoded by a medium size (1.5–2.4 Kb) M dsRNA virus, maintained by a larger helper virus generally called L-A (4.6 Kb). Different types of L-A are found associated to specific Ms: L-A in K1 strains and L-A-2 in K2 strains. Here, we extend the analysis of L-A helper viruses to yeasts other than S. cerevisiae, namely S. paradoxus, S. uvarum and S. kudriavzevii. Our sequencing data from nine new L-A variants confirm the specific association of each toxin-producing M and its helper virus, suggesting co-evolution. Their nucleotide sequences vary from 10% to 30% and the variation seems to depend on the geographical location of the hosts, suggesting cross-species transmission between species in the same habitat. Finally, we transferred by genetic methods different killer viruses from S. paradoxus into S. cerevisiae or viruses from S. cerevisiae into S. uvarum or S. kudriavzevii. In the foster hosts, we observed no impairment for their stable transmission and maintenance, indicating that the requirements for virus amplification in these species are essentially the same. We also characterized new killer toxins from S. paradoxus and constructed “superkiller” strains expressing them. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Open AccessFeature PaperArticle
New Insights into the Genome Organization of Yeast Killer Viruses Based on “Atypical” Killer Strains Characterized by High-Throughput Sequencing
Received: 31 August 2017 / Revised: 15 September 2017 / Accepted: 16 September 2017 / Published: 19 September 2017
Cited by 4 | PDF Full-text (1870 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Viral M-dsRNAs encoding yeast killer toxins share similar genomic organization, but no overall sequence identity. The dsRNA full-length sequences of several known M-viruses either have yet to be completed, or they were shorter than estimated by agarose gel electrophoresis. High-throughput sequencing was used [...] Read more.
Viral M-dsRNAs encoding yeast killer toxins share similar genomic organization, but no overall sequence identity. The dsRNA full-length sequences of several known M-viruses either have yet to be completed, or they were shorter than estimated by agarose gel electrophoresis. High-throughput sequencing was used to analyze some M-dsRNAs previously sequenced by traditional techniques, and new dsRNAs from atypical killer strains of Saccharomyces cerevisiae and Torulaspora delbrueckii. All dsRNAs expected to be present in a given yeast strain were reliably detected and sequenced, and the previously-known sequences were confirmed. The few discrepancies between viral variants were mostly located around the central poly(A) region. A continuous sequence of the ScV-M2 genome was obtained for the first time. M1 virus was found for the first time in wine yeasts, coexisting with Mbarr-1 virus in T. delbrueckii. Extra 5′- and 3′-sequences were found in all M-genomes. The presence of repeated short sequences in the non-coding 3′-region of most M-genomes indicates that they have a common phylogenetic origin. High identity between amino acid sequences of killer toxins and some unclassified proteins of yeast, bacteria, and wine grapes suggests that killer viruses recruited some sequences from the genome of these organisms, or vice versa, during evolution. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Open AccessFeature PaperCommunication
Use of a Yeast tRNase Killer Toxin to Diagnose Kti12 Motifs Required for tRNA Modification by Elongator
Received: 31 July 2017 / Revised: 29 August 2017 / Accepted: 3 September 2017 / Published: 5 September 2017
Cited by 6 | PDF Full-text (5304 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex from Kluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin’s action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1-Elp6). Hence, [...] Read more.
Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex from Kluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin’s action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1-Elp6). Hence, loss of anticodon modification in mutants lacking Elongator or related KTI (K. lactis Toxin Insensitive) genes protects against tRNA cleavage and confers resistance to the toxin. Here, we show that zymocin can be used as a tool to genetically analyse KTI12, a gene previously shown to code for an Elongator partner protein. From a kti12 mutant pool of zymocin survivors, we identify motifs in Kti12 that are functionally directly coupled to Elongator activity. In addition, shared requirement of U34 modifications for nonsense and missense tRNA suppression (SUP4; SOE1) strongly suggests that Kti12 and Elongator cooperate to assure proper tRNA functioning. We show that the Kti12 motifs are conserved in plant ortholog DRL1/ELO4 from Arabidopsis thaliana and seem to be involved in binding of cofactors (e.g., nucleotides, calmodulin). Elongator interaction defects triggered by mutations in these motifs correlate with phenotypes typical for loss of U34 modification. Thus, tRNA modification by Elongator appears to require physical contact with Kti12, and our preliminary data suggest that metabolic signals may affect proper communication between them. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Open AccessArticle
Different Metabolic Pathways Are Involved in Response of Saccharomyces cerevisiae to L-A and M Viruses
Received: 30 June 2017 / Revised: 17 July 2017 / Accepted: 21 July 2017 / Published: 25 July 2017
Cited by 2 | PDF Full-text (5361 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Competitive and naturally occurring yeast killer phenotype is governed by coinfection with dsRNA viruses. Long-term relationship between the host cell and viruses appear to be beneficial and co-adaptive; however, the impact of viral dsRNA on the host gene expression has barely been investigated. [...] Read more.
Competitive and naturally occurring yeast killer phenotype is governed by coinfection with dsRNA viruses. Long-term relationship between the host cell and viruses appear to be beneficial and co-adaptive; however, the impact of viral dsRNA on the host gene expression has barely been investigated. Here, we determined the transcriptomic profiles of the host Saccharomyces cerevisiae upon the loss of the M-2 dsRNA alone and the M-2 along with the L-A-lus dsRNAs. We provide a comprehensive study based on the high-throughput RNA-Seq data, Gene Ontology and the analysis of the interaction networks. We identified 486 genes differentially expressed after curing yeast cells of the M-2 dsRNA and 715 genes affected by the elimination of both M-2 and L-A-lus dsRNAs. We report that most of the transcriptional responses induced by viral dsRNAs are moderate. Differently expressed genes are related to ribosome biogenesis, mitochondrial functions, stress response, biosynthesis of lipids and amino acids. Our study also provided insight into the virus–host and virus–virus interplays. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Review

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Open AccessFeature PaperReview
Yeast Killer Toxin K28: Biology and Unique Strategy of Host Cell Intoxication and Killing
Toxins 2017, 9(10), 333; https://doi.org/10.3390/toxins9100333
Received: 29 September 2017 / Revised: 12 October 2017 / Accepted: 17 October 2017 / Published: 20 October 2017
Cited by 6 | PDF Full-text (4121 KB) | HTML Full-text | XML Full-text | Correction
Abstract
The initial discovery of killer toxin-secreting brewery strains of Saccharomyces cerevisiae (S. cerevisiae) in the mid-sixties of the last century marked the beginning of intensive research in the yeast virology field. So far, four different S. cerevisiae killer toxins (K28, K1, [...] Read more.
The initial discovery of killer toxin-secreting brewery strains of Saccharomyces cerevisiae (S. cerevisiae) in the mid-sixties of the last century marked the beginning of intensive research in the yeast virology field. So far, four different S. cerevisiae killer toxins (K28, K1, K2, and Klus), encoded by cytoplasmic inherited double-stranded RNA viruses (dsRNA) of the Totiviridae family, have been identified. Among these, K28 represents the unique example of a yeast viral killer toxin that enters a sensitive cell by receptor-mediated endocytosis to reach its intracellular target(s). This review summarizes and discusses the most recent advances and current knowledge on yeast killer toxin K28, with special emphasis on its endocytosis and intracellular trafficking, pointing towards future directions and open questions in this still timely and fascinating field of killer yeast research. Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Open AccessFeature PaperEditor’s ChoiceReview
The Biology of Pichia membranifaciens Killer Toxins
Received: 10 February 2017 / Revised: 7 March 2017 / Accepted: 20 March 2017 / Published: 23 March 2017
Cited by 10 | PDF Full-text (3078 KB) | HTML Full-text | XML Full-text
Abstract
The killer phenomenon is defined as the ability of some yeast to secrete toxins that are lethal to other sensitive yeasts and filamentous fungi. Since the discovery of strains of Saccharomyces cerevisiae capable of secreting killer toxins, much information has been gained regarding [...] Read more.
The killer phenomenon is defined as the ability of some yeast to secrete toxins that are lethal to other sensitive yeasts and filamentous fungi. Since the discovery of strains of Saccharomyces cerevisiae capable of secreting killer toxins, much information has been gained regarding killer toxins and this fact has substantially contributed knowledge on fundamental aspects of cell biology and yeast genetics. The killer phenomenon has been studied in Pichia membranifaciens for several years, during which two toxins have been described. PMKT and PMKT2 are proteins of low molecular mass that bind to primary receptors located in the cell wall structure of sensitive yeast cells, linear (1→6)-β-d-glucans and mannoproteins for PMKT and PMKT2, respectively. Cwp2p also acts as a secondary receptor for PMKT. Killing of sensitive cells by PMKT is characterized by ionic movements across plasma membrane and an acidification of the intracellular pH triggering an activation of the High Osmolarity Glycerol (HOG) pathway. On the contrary, our investigations showed a mechanism of killing in which cells are arrested at an early S-phase by high concentrations of PMKT2. However, we concluded that induced mortality at low PMKT2 doses and also PMKT is indeed of an apoptotic nature. Killer yeasts and their toxins have found potential applications in several fields: in food and beverage production, as biocontrol agents, in yeast bio-typing, and as novel antimycotic agents. Accordingly, several applications have been found for P. membranifaciens killer toxins, ranging from pre- and post-harvest biocontrol of plant pathogens to applications during wine fermentation and ageing (inhibition of Botrytis cinerea, Brettanomyces bruxellensis, etc.). Full article
(This article belongs to the Special Issue Yeast Killer Toxins)
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Other

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Open AccessCorrection
Correction: Becker, B. et al. Yeast Killer Toxin K28: Biology and Unique Strategy of Host Cell Intoxication and Killing
Received: 12 March 2018 / Revised: 13 March 2018 / Accepted: 13 March 2018 / Published: 23 March 2018
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(This article belongs to the Special Issue Yeast Killer Toxins)
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