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Special Issue "Toxin-Antitoxin System"

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

Deadline for manuscript submissions: closed (31 October 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Laurence Van Melderen

Laboratoire de Génétique et Physiologie Bactérienne, Faculté de Sciences, IBMM, Université Libre de Bruxelles (ULB), Gosselies, B-6041, Belgium

Special Issue Information

Dear Colleagues,

Toxin-antitoxin (TA) systems are small genetic modules encoding a stable toxic protein and its cognate unstable antitoxin, which can be either RNA or protein. Five TA types are currently recognized, among them type II systems are probably the best documented. TA systems are surprisingly abundant in eubacterial and archeal genomes. TA systems were originally discovered on plasmids in the mid 1980s. Their function when located on such mobile genetic elements is to contribute to their stability by a phenomenon denoted as addiction (or post-segregational killing). Addiction relies on the differential stability of the antitoxin and toxin components. In daughter-bacteria that did not receive a plasmid copy at cell division, antitoxins are degraded and as a consequence toxins are released from inhibition thereby leading to the killing of plasmid-free cells. Homologues of plasmidic systems as well as novel types of TA systems were subsequently found in chromosomes and for some of them extensively studied. The biological role of these systems is still under debate and conflicting hypotheses have been proposed, at least for type II systems, from persistence to stabilization of large genomic islands or competition between mobile genetic elements. TA systems might also operate at the selfish level to promote their own dissemination in bacterial genomes although in certain conditions, at the expense of host survival. In addition to the functional aspects, essential questions regarding these diverse and mysterious genetic entities remain to be answered such as their origin and evolution and maybe the most intriguing which concerns the basis of their evolutionary success.

Prof. Dr. Laurence Van Melderen
Guest Editor

 

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Keywords

  • endoribonuclease
  • selfish genes
  • programmed cell death
  • biofilm formation
  • stress responses
  • DNA-gyrase inhibitor
  • translation inhibition

Related Special Issue

Published Papers (6 papers)

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Research

Jump to: Review

Open AccessArticle Coupling between the Basic Replicon and the Kis-Kid Maintenance System of Plasmid R1: Modulation by Kis Antitoxin Levels and Involvement in Control of Plasmid Replication
Toxins 2015, 7(2), 478-492; doi:10.3390/toxins7020478
Received: 7 November 2014 / Revised: 17 December 0214 / Accepted: 29 January 2015 / Published: 5 February 2015
Cited by 1 | PDF Full-text (846 KB) | HTML Full-text | XML Full-text
Abstract
kis-kid, the auxiliary maintenance system of plasmid R1 and copB, the auxiliary copy number control gene of this plasmid, contribute to increase plasmid replication efficiency in cells with lower than average copy number. It is thought that Kis antitoxin levels [...] Read more.
kis-kid, the auxiliary maintenance system of plasmid R1 and copB, the auxiliary copy number control gene of this plasmid, contribute to increase plasmid replication efficiency in cells with lower than average copy number. It is thought that Kis antitoxin levels decrease in these cells and that this acts as the switch that activates the Kid toxin; activated Kid toxin reduces copB-mRNA levels and this increases RepA levels that increases plasmid copy number. In support of this model we now report that: (i) the Kis antitoxin levels do decrease in cells containing a mini-R1 plasmid carrying a repA mutation that reduces plasmid copy number; (ii) kid-dependent replication rescue is abolished in cells in which the Kis antitoxin levels or the CopB levels are increased. Unexpectedly we found that this coordination significantly increases both the copy number of the repA mutant and of the wt mini-R1 plasmid. This indicates that the coordination between plasmid replication functions and kis-kid system contributes significantly to control plasmid R1 replication. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)
Open AccessArticle Toxin ζ Reversible Induces Dormancy and Reduces the UDP-N-Acetylglucosamine Pool as One of the Protective Responses to Cope with Stress
Toxins 2014, 6(9), 2787-2803; doi:10.3390/toxins6092787
Received: 18 June 2014 / Revised: 14 August 2014 / Accepted: 9 September 2014 / Published: 18 September 2014
Cited by 5 | PDF Full-text (766 KB) | HTML Full-text | XML Full-text
Abstract
Toxins of the ζ/PezT family, found in the genome of major human pathogens, phosphorylate the peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (UNAG) leading to unreactive UNAG-3P. Transient over-expression of a PezT variant impairs cell wall biosynthesis and triggers autolysis in Escherichia coli [...] Read more.
Toxins of the ζ/PezT family, found in the genome of major human pathogens, phosphorylate the peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (UNAG) leading to unreactive UNAG-3P. Transient over-expression of a PezT variant impairs cell wall biosynthesis and triggers autolysis in Escherichia coli. Conversely, physiological levels of ζ reversibly induce dormancy produce a sub-fraction of membrane-compromised cells, and a minor subpopulation of Bacillus subtilis cells become tolerant of toxin action. We report here that purified ζ is a strong UNAG-dependent ATPase, being GTP a lower competitor. In vitro, ζ toxin phosphorylates a fraction of UNAG. In vivo, ζ-mediated inactivation of UNAG by phosphorylation does not deplete the active UNAG pool, because expression of the toxin enhances the efficacy of genuine cell wall inhibitors (fosfomycin, vancomycin or ampicillin). Transient ζ expression together with fosfomycin treatment halt cell proliferation, but ε2 antitoxin expression facilitates the exit of ζ-induced dormancy, suggesting that there is sufficient UNAG for growth. We propose that ζ induces diverse cellular responses to cope with stress, being the reduction of the UNAG pool one among them. If the action of ζ is not inhibited, e.g., by de novo ε2 antitoxin synthesis, the toxin markedly enhances the efficacy of antimicrobial treatment without massive autolysis in Firmicutes. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)
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Review

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Open AccessReview sRNA Antitoxins: More than One Way to Repress a Toxin
Toxins 2014, 6(8), 2310-2335; doi:10.3390/toxins6082310
Received: 30 June 2014 / Revised: 15 July 2014 / Accepted: 17 July 2014 / Published: 4 August 2014
Cited by 9 | PDF Full-text (357 KB) | HTML Full-text | XML Full-text
Abstract
Bacterial toxin-antitoxin loci consist of two genes: one encodes a potentially toxic protein, and the second, an antitoxin to repress its function or expression. The antitoxin can either be an RNA or a protein. For type I and type III loci, the [...] Read more.
Bacterial toxin-antitoxin loci consist of two genes: one encodes a potentially toxic protein, and the second, an antitoxin to repress its function or expression. The antitoxin can either be an RNA or a protein. For type I and type III loci, the antitoxins are RNAs; however, they have very different modes of action. Type I antitoxins repress toxin protein expression through interacting with the toxin mRNA, thereby targeting the mRNA for degradation or preventing its translation or both; type III antitoxins directly bind to the toxin protein, sequestering it. Along with these two very different modes of action for the antitoxin, there are differences in the functions of the toxin proteins and the mobility of these loci between species. Within this review, we discuss the major differences as to how the RNAs repress toxin activity, the potential consequences for utilizing different regulatory strategies, as well as the confirmed and potential biological roles for these loci across bacterial species. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)
Open AccessReview Multiple Toxin-Antitoxin Systems in Mycobacterium tuberculosis
Toxins 2014, 6(3), 1002-1020; doi:10.3390/toxins6031002
Received: 19 December 2013 / Revised: 20 February 2014 / Accepted: 24 February 2014 / Published: 6 March 2014
Cited by 24 | PDF Full-text (2015 KB) | HTML Full-text | XML Full-text
Abstract
The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the [...] Read more.
The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the persistence phase are poorly understood. Remarkably, M. tuberculosis possesses a very high number of toxin-antitoxin (TA) systems in its chromosome, 79 in total, regrouping both well-known (68) and novel (11) families, with some of them being strongly induced in drug-tolerant persisters. In agreement with the capacity of stress-responsive TA systems to generate persisters in other bacteria, it has been proposed that activation of TA systems in M. tuberculosis could contribute to its pathogenesis. Herein, we review the current knowledge on the multiple TA families present in this bacterium, their mechanism, and their potential role in physiology and virulence. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)
Open AccessReview Regulating Toxin-Antitoxin Expression: Controlled Detonation of Intracellular Molecular Timebombs
Toxins 2014, 6(1), 337-358; doi:10.3390/toxins6010337
Received: 6 December 2013 / Revised: 20 December 2013 / Accepted: 8 January 2014 / Published: 15 January 2014
Cited by 16 | PDF Full-text (830 KB) | HTML Full-text | XML Full-text
Abstract
Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic [...] Read more.
Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, biofilm formation, and bacteriophage resistance. Among the ever increasing number of TA modules that have been identified, the most numerous are complexes in which both toxin and antitoxin are proteins. Transcriptional autoregulation of the operons encoding these complexes is key to ensuring balanced TA production and to prevent inadvertent toxin release. Control typically is exerted by binding of the antitoxin to regulatory sequences upstream of the operons. The toxin protein commonly works as a transcriptional corepressor that remodels and stabilizes the antitoxin. However, there are notable exceptions to this paradigm. Moreover, it is becoming clear that TA complexes often form one strand in an interconnected web of stress responses suggesting that their transcriptional regulation may prove to be more intricate than currently understood. Furthermore, interference with TA gene transcriptional autoregulation holds considerable promise as a novel antibacterial strategy: artificial release of the toxin factor using designer drugs is a potential approach to induce bacterial suicide from within. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)
Open AccessReview Toxin-Antitoxin Systems as Multilevel Interaction Systems
Toxins 2014, 6(1), 304-324; doi:10.3390/toxins6010304
Received: 2 December 2013 / Revised: 19 December 2013 / Accepted: 27 December 2013 / Published: 10 January 2014
Cited by 50 | PDF Full-text (324 KB) | HTML Full-text | XML Full-text
Abstract
Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence [...] Read more.
Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to DNA stabilization or protection against mobile genetic elements. They are classified in five types, depending on the nature and mode of action of the antitoxin. In type I and III, antitoxins are RNAs that either inhibit the synthesis of the toxin or sequester it. In type II, IV and V, antitoxins are proteins that either sequester, counterbalance toxin activity or inhibit toxin synthesis. In addition to these interactions between the antitoxin and toxin components (RNA-RNA, protein-protein, RNA-protein), TA systems interact with a variety of cellular factors, e.g., toxins target essential cellular components, antitoxins are degraded by RNAses or ATP-dependent proteases. Hence, TA systems have the capacity to interact with each other at different levels. In this review, we will discuss the different interactions in which TA systems are involved and their implications in TA system functions and evolution. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)

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