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Brice Felden - One of the best experts on this subject based on the ideXlab platform.

  • Cross-Regulations between Bacterial Toxin-Antitoxin Systems: Evidence of an Interconnected Regulatory Network?
    Trends in Microbiology, 2020
    Co-Authors: Camille Riffaud, Marie-laure Pinel-marie, Brice Felden
    Abstract:

    Toxin-Antitoxin (TA) systems are ubiquitous among bacteria and include stable toxins whose toxicity can be counteracted by RNA or protein Antitoxins. They are involved in multiple functions that range from stability maintenance for mobile genetic elements to stress adaptation. Bacterial chromosomes frequently have multiple homologues of TA system loci, and it is unclear why there are so many of them. In this review we focus on cross-regulations between TA systems, which occur between both homologous and nonhomologous systems, from similar or distinct types, whether encoded from plasmids or chromosomes. In addition to being able to modulate RNA expression levels, cross-regulations between these systems can also influence their toxicity. This suggests the idea that they are involved in an interconnected regulatory network.

  • A novel Staphylococcus aureus cis-trans type I toxin-Antitoxin module with dual effects on bacteria and host cells
    Nucleic Acids Research, 2019
    Co-Authors: Noëlla Germain-amiot, Yoann Augagneur, Emilie Camberlein, Irène Nicolas, Valérie Lecureur, Astrid Rouillon, Brice Felden
    Abstract:

    Bacterial type I toxin-Antitoxin (TA) systems are widespread, and consist of a stable toxic peptide whose expression is monitored by a labile RNA Antitoxin. We characterized Staphylococcus aureus SprA2/SprA2AS module, which shares nucleotide similarities with the SprA1/SprA1AS TA system. We demonstrated that SprA2/SprA2AS encodes a functional type I TA system, with the cis-encoded SprA2AS Antitoxin acting in trans to prevent ribosomal loading onto SprA2 RNA. We proved that both TA systems are distinct, with no cross-regulation between the Antitoxins in vitro or in vivo. SprA2 expresses PepA2, a toxic peptide which internally triggers bacterial death. Conversely, although PepA2 does not affect bacteria when it is present in the extracellular medium, it is highly toxic to other host cells such as polymorphonuclear neutrophils and erythrocytes. Finally, we showed that SprA2AS expression is lowered during osmotic shock and stringent response, which indicates that the system responds to specific triggers. Therefore, the SprA2/SprA2AS module is not redundant with SprA1/SprA1AS, and its PepA2 peptide exhibits an original dual mode of action against bacteria and host cells. This suggests an altruistic behavior for S. aureus in which clones producing PepA2 in vivo shall die as they induce cytotoxicity, thereby promoting the success of the community.

  • Functionality and cross-regulation of the four SprG/SprF type I toxin-Antitoxin systems in Staphylococcus aureus
    Nucleic Acids Research, 2019
    Co-Authors: Camille Riffaud, Marie-laure Pinel-marie, Gaetan Pascreau, Brice Felden
    Abstract:

    Toxin-Antitoxin (TA) systems are ubiquitous among bacteria, frequently expressed in multiple copies, and important for functions such as antibiotic resistance and persistence. Type I TA systems are composed of a stable toxic peptide whose expression is repressed by an unstable RNA Antitoxin. Here, we investigated the functionalities, regulation, and possible cross-talk between three core genome copies of the pathogenicity island-encoded sprG1/sprF1' type I TA system in the human pathogen Staphylococcus aureus. Except for SprG4, all RNA from these pairs, sprG2/sprF2, sprG3/sprF3, sprG4/sprF4, are expressed in the HG003 strain. SprG2 and SprG3 RNAs encode toxic peptides whose overexpression triggers bacteriostasis, which is counteracted at the RNA level by the overexpression of SprF2 and SprF3 Antitoxins. Complex formation between each toxin and its cognate Antitoxin involves their overlapping 3 ends, and each SprF Antitoxin specifically neutralizes the toxicity of its cognate SprG toxin without cross-talk. However, overexpression studies suggest cross-regulations occur at the RNA level between the SprG/SprF TA systems during growth. When subjected to H2O2-induced oxidative stress, almost all Antitoxin levels dropped, while only SprG1 and SprF1 were reduced during phagocytosis-induced oxidative stress. SprG1, SprF1, SprF2, SprG3and SprF3 levels also decrease during hyperosmotic stress. This suggests that novel SprG/SprF TA systems are involved in S. aureus persistence.

  • Linking bacterial type I toxins with their actions
    Current Opinion in Microbiology, 2016
    Co-Authors: Régine Brielle, Marie-laure Pinel-marie, Brice Felden
    Abstract:

    Bacterial type I toxin–Antitoxin systems consist of stable toxin-encoding mRNAs whose expression is counteracted by unstable RNA Antitoxins. Accumulating evidence suggests that these players belong to broad regulatory networks influencing overall bacterial physiology. The majority of known transmembrane type I toxic peptides have conserved structural characteristics. However, recent studies demonstrated that their mechanisms of toxicity are diverse and complex. To better assess the current state of the art, type I toxins can be grouped into two classes according to their location and mechanisms of action: membrane-associated toxins acting by pore formation and/or by nucleoid condensation; and cytosolic toxins inducing nucleic acid cleavage. This classification will evolve as a result of future investigations.

  • Functional and structural insights of a Staphylococcus aureus apoptotic-like membrane peptide from a toxin-Antitoxin module.
    Journal of Biological Chemistry, 2012
    Co-Authors: Nour Sayed, Sylvie Nonin-lecomte, Stephane Rety, Brice Felden
    Abstract:

    We report a functional type I toxin-Antitoxin (TA) module expressed by a human pathogen, Staphylococcus aureus. TA systems consist of stable toxins and labile Antitoxins encoded within small genetic modules widespread in eubacteria and archaea. TA genes provide stress adaptation and protection against DNA loss or invasion. The genes encoding the SprA1 toxic peptide (PepA1) and the SprA1(AS) RNA Antitoxin are within a pathogenicity island on opposite strands and possess a 3' overlap. To prevent peptide toxicity during S. aureus growth, PepA1 expression from stable (half-life > 3 h) SprA1 is repressed by elevated amounts of unstable (half-life = ∼10 mn) SprA1(AS). In vivo, PepA1 localizes at the bacterial membrane and triggers S. aureus death. Based on NMR and CD data, its solution structure was solved and is a long bent, interrupted helix. Molecular dynamics simulations indicate that PepA1 compaction and helical content fluctuate in accordance with its cytoplasm or membrane location. When inserted into the S. aureus membrane, the PepA1 conformation switches to a ∼7-nm-long continuous helix, presumably forming pores to alter membrane integrity. PepA1 expression is induced upon acidic and oxidative stresses by reducing SprA1(AS) levels. As an altruistic behavior during infection, some cells may induce the expression of that toxin that would facilitate departure from the host immune cells for spreading.

Laurence Van Melderen - One of the best experts on this subject based on the ideXlab platform.

  • The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems
    Frontiers in Genetics, 2020
    Co-Authors: Dukas Jurėnas, Laurence Van Melderen
    Abstract:

    Type II Toxin-Antitoxin (TA) modules are bacterial operons that encode a toxic protein and its antidote, which form a self-regulating genetic system. Antitoxins put a halter on toxins in many ways that distinguish different types of TA modules. In type II TA modules, toxin and Antitoxin are proteins that form a complex which physically sequesters the toxin, thereby preventing its toxic activity. Type II toxins inhibit various cellular processes, however, the translation process appears to be their favorite target and nearly every step of this complex process is inhibited by type II toxins. The structural features, enzymatic activities and target specificities of the different toxin families are discussed. Finally, this review emphasizes that the structural folds presented by these toxins are not restricted to type II TA toxins or to one particular cellular target, and discusses why so many of them evolved to target translation as well as the recent developments regarding the role(s) of these systems in bacterial physiology and evolution.

  • Toxin-Antitoxin systems and persistence
    Persister Cells and Infectious Disease, 2019
    Co-Authors: Nathan Fraikin, Frédéric Goormaghtigh, Laurence Van Melderen
    Abstract:

    Toxin-Antitoxin (TA) systems are small genetic modules comprising a stable toxic protein and an Antitoxin preventing the toxin activity. In type II TA systems, Antitoxins are unstable proteins that are degraded by host ATP-dependent proteases. In steady-state conditions, the Antitoxin forms a complex with the toxin in which the toxic activity is inactivated, this complex also being responsible for negative autoregulation of the system. Environmental or physiological conditions generating a imbalanced toxin:Antitoxin ratio should induce TA systems and halt cell growth. Persistence has been linked to type II TA systems activation in Escherichia coli K-12 via a complex regulatory cascade involving Antitoxin degradation by the Lon protease, polyphosphate, and (p)ppGpp. However, this model has been recently disproved questioning the involvement of type II TA systems in persistence, at least in the E. coli K-12 model. In this chapter, we discuss the relevant data linking type II TA systems and persistence in E. coli and other bacterial species.

  • Small-angle X-ray scattering- and nuclear magnetic resonance-derived conformational ensemble of the highly flexible Antitoxin PaaA2.
    Structure (London England : 1993), 2014
    Co-Authors: Yann G J Sterckx, Laurence Van Melderen, Abel Garcia-pino, Alexander N Volkov, Wim F Vranken, Jaka Kragelj, Malene Ringkjøbing Jensen, Lieven Buts, Thomas Jové, Martin Blackledge
    Abstract:

    Antitoxins from prokaryotic type II toxin-Antitoxin modules are characterized by a high degree of intrinsic disorder. The description of such highly flexible proteins is challenging because they cannot be represented by a single structure. Here, we present a combination of SAXS and NMR data to describe the conformational ensemble of the PaaA2 Antitoxin from the human pathogen E. coli O157. The method encompasses the use of SAXS data to filter ensembles out of a pool of conformers generated by a custom NMR structure calculation protocol and the subsequent refinement by a block jackknife procedure. The final ensemble obtained through the method is validated by an established residual dipolar coupling analysis. We show that the conformational ensemble of PaaA2 is highly compact and that the protein exists in solution as two preformed helices, connected by a flexible linker, that probably act as molecular recognition elements for toxin inhibition.

  • Toxin-Antitoxin systems as multilevel interaction systems.
    Toxins, 2014
    Co-Authors: Nathalie Goeders, Laurence Van Melderen
    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 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.

  • diversity of bacterial type ii toxin Antitoxin systems a comprehensive search and functional analysis of novel families
    Nucleic Acids Research, 2011
    Co-Authors: Raphael Leplae, Damien Geeraerts, Regis Hallez, Julien Guglielmini, Pierrealexandre Dreze, Laurence Van Melderen
    Abstract:

    Type II toxin-Antitoxin (TA) systems are generally composed of two genes organized in an operon, encoding a labile Antitoxin and a stable toxin. They were first discovered on plasmids where they contribute to plasmid stability by a phenomenon denoted as 'addiction', and subsequently in bacterial chromosomes. To discover novel families of Antitoxins and toxins, we developed a bioinformatics approach based on the 'guilt by association' principle. Extensive experimental validation in Escherichia coli of predicted Antitoxins and toxins increased significantly the number of validated systems and defined novel toxin and Antitoxin families. Our data suggest that toxin families as well as Antitoxin families originate from distinct ancestors that were assembled multiple times during evolution. Toxin and Antitoxin families found on plasmids tend to be promiscuous and widespread, indicating that TA systems move through horizontal gene transfer. We propose that due to their addictive properties, TA systems are likely to be maintained in chromosomes even though they do not necessarily confer an advantage to their bacterial hosts. Therefore, addiction might play a major role in the evolutionary success of TA systems both on mobile genetic elements and in bacterial chromosomes.

Eugene V Koonin - One of the best experts on this subject based on the ideXlab platform.

  • comprehensive comparative genomic analysis of type 2 toxin Antitoxin systems and related mobile stress response systems in prokaryotes
    Biology Direct, 2009
    Co-Authors: Kira S Makarova, Yuri I Wolf, Eugene V Koonin
    Abstract:

    Background: The prokaryotic toxin-Antitoxin systems (TAS, also referred to as TA loci) are widespread, mobile two-gene modules that can be viewed as selfish genetic elements because they evolved mechanisms to become addictive for replicons and cells in which they reside, but also possess "normal" cellular functions in various forms of stress response and management of prokaryotic population. Several distinct TAS of type 1, where the toxin is a protein and the Antitoxin is an antisense RNA, and numerous, unrelated TAS of type 2, in which both the toxin and the Antitoxin are proteins, have been experimentally characterized, and it is suspected that many more remain to be identified. Results: We report a comprehensive comparative-genomic analysis of Type 2 toxin-Antitoxin systems in prokaryotes. Using sensitive methods for distant sequence similarity search, genome context analysis and a new approach for the identification of mobile two-component systems, we identified numerous, previously unnoticed protein families that are homologous to toxins and Antitoxins of known type 2 TAS. In addition, we predict 12 new families of toxins and 13 families of Antitoxins, and also, predict a TAS or TAS-like activity for several gene modules that were not previously suspected to function in that capacity. In particular, we present indications that the two-gene module that encodes a minimal nucleotidyl transferase and the accompanying HEPN protein, and is extremely abundant in many archaea and bacteria, especially, thermophiles might comprise a novel TAS. We present a survey of previously known and newly predicted TAS in 750 complete genomes of archaea and bacteria, quantitatively demonstrate the exceptional mobility of the TAS, and explore the network of toxin-Antitoxin pairings that combines plasticity with selectivity. Conclusion: The defining properties of the TAS, namely, the typically small size of the toxin and Antitoxin genes, fast evolution, and extensive horizontal mobility, make the task of comprehensive identification of these systems particularly challenging. However, these same properties can be exploited to develop context-based computational approaches which, combined with exhaustive analysis of subtle sequence similarities were employed in this work to substantially expand the current collection of TAS by predicting both previously unnoticed, derived versions of known toxins and Antitoxins, and putative novel TAS-like systems. In a broader context, the TAS belong to the resistome domain of the prokaryotic mobilome which includes partially selfish, addictive gene cassettes involved in various aspects of stress response and organized under the same general principles as the TAS. The "selfish altruism", or "responsible selfishness", of TAS-like systems appears to be a defining feature of the resistome and an important characteristic of the entire prokaryotic pan-genome given that in the prokaryotic world the mobilome and the "stable" chromosomes form a dynamic continuum.

  • Comprehensive comparative-genomic analysis of Type 2 toxin-Antitoxin systems and related mobile stress response systems in prokaryotes
    Biology Direct, 2009
    Co-Authors: Kira S Makarova, Yuri I Wolf, Eugene V Koonin
    Abstract:

    Background The prokaryotic toxin-Antitoxin systems (TAS, also referred to as TA loci) are widespread, mobile two-gene modules that can be viewed as selfish genetic elements because they evolved mechanisms to become addictive for replicons and cells in which they reside, but also possess "normal" cellular functions in various forms of stress response and management of prokaryotic population. Several distinct TAS of type 1, where the toxin is a protein and the Antitoxin is an antisense RNA, and numerous, unrelated TAS of type 2, in which both the toxin and the Antitoxin are proteins, have been experimentally characterized, and it is suspected that many more remain to be identified. Results We report a comprehensive comparative-genomic analysis of Type 2 toxin-Antitoxin systems in prokaryotes. Using sensitive methods for distant sequence similarity search, genome context analysis and a new approach for the identification of mobile two-component systems, we identified numerous, previously unnoticed protein families that are homologous to toxins and Antitoxins of known type 2 TAS. In addition, we predict 12 new families of toxins and 13 families of Antitoxins, and also, predict a TAS or TAS-like activity for several gene modules that were not previously suspected to function in that capacity. In particular, we present indications that the two-gene module that encodes a minimal nucleotidyl transferase and the accompanying HEPN protein, and is extremely abundant in many archaea and bacteria, especially, thermophiles might comprise a novel TAS. We present a survey of previously known and newly predicted TAS in 750 complete genomes of archaea and bacteria, quantitatively demonstrate the exceptional mobility of the TAS, and explore the network of toxin-Antitoxin pairings that combines plasticity with selectivity. Conclusion The defining properties of the TAS, namely, the typically small size of the toxin and Antitoxin genes, fast evolution, and extensive horizontal mobility, make the task of comprehensive identification of these systems particularly challenging. However, these same properties can be exploited to develop context-based computational approaches which, combined with exhaustive analysis of subtle sequence similarities were employed in this work to substantially expand the current collection of TAS by predicting both previously unnoticed, derived versions of known toxins and Antitoxins, and putative novel TAS-like systems. In a broader context, the TAS belong to the resistome domain of the prokaryotic mobilome which includes partially selfish, addictive gene cassettes involved in various aspects of stress response and organized under the same general principles as the TAS. The "selfish altruism", or "responsible selfishness", of TAS-like systems appears to be a defining feature of the resistome and an important characteristic of the entire prokaryotic pan-genome given that in the prokaryotic world the mobilome and the "stable" chromosomes form a dynamic continuum. Reviewers This paper was reviewed by Kenn Gerdes (nominated by Arcady Mushegian), Daniel Haft, Arcady Mushegian, and Andrei Osterman. For full reviews, go to the Reviewers' Reports section.

Joanna Trylska - One of the best experts on this subject based on the ideXlab platform.

  • Artificial Activation of Escherichia coli mazEF and hipBA Toxin–Antitoxin Systems by Antisense Peptide Nucleic Acids as an Antibacterial Strategy
    Frontiers in Microbiology, 2018
    Co-Authors: Marcin Równicki, Tomasz Pieńko, Jakub Czarnecki, Monika Kolanowska, Dariusz Bartosik, Joanna Trylska
    Abstract:

    The search for new, non-standard targets is currently a high priority in the design of new antibacterial compounds. Bacterial toxin-Antitoxin systems (TAs) are genetic modules that encode a toxin protein that causes growth arrest by interfering with essential cellular processes, and a cognate Antitoxin, which neutralizes the toxin activity. TAs have no human analogues, are highly abundant in bacterial genomes, and therefore represent attractive alternative targets for antimicrobial drugs. This study demonstrates how artificial activation of Escherichia coli mazEF and hipBA toxin-Antitoxin systems using sequence-specific antisense peptide nucleic acid oligomers is an innovative antibacterial strategy. The growth arrest observed in E. coli resulted from the inhibition of translation of the Antitoxins by the antisense oligomers. Furthermore, two other targets, related to the activities of mazEF and hipBA, were identified as promising sites of action for antibacterials. These results show that TAs are susceptible to sequence-specific antisense agents and provide a proof-of-concept for their further exploitation in antimicrobial strategies.

  • artificial activation of escherichia coli mazef and hipba toxin Antitoxin systems by antisense peptide nucleic acids as an antibacterial strategy
    Frontiers in Microbiology, 2018
    Co-Authors: Marcin Równicki, Jakub Czarnecki, Monika Kolanowska, Dariusz Bartosik, Tomasz Pienko, Joanna Trylska
    Abstract:

    The search for new, non-standard targets is currently a high priority in the design of new antibacterial compounds. Bacterial toxin-Antitoxin systems (TAs) are genetic modules that encode a toxin protein that causes growth arrest by interfering with essential cellular processes, and a cognate Antitoxin, which neutralizes the toxin activity. TAs have no human analogues, are highly abundant in bacterial genomes, and therefore represent attractive alternative targets for antimicrobial drugs. This study demonstrates how artificial activation of Escherichia coli mazEF and hipBA toxin-Antitoxin systems using sequence-specific antisense peptide nucleic acid oligomers is an innovative antibacterial strategy. The growth arrest observed in E. coli resulted from the inhibition of translation of the Antitoxins by the antisense oligomers. Furthermore, two other targets, related to the activities of mazEF and hipBA, were identified as promising sites of action for antibacterials. These results show that TAs are susceptible to sequence-specific antisense agents and provide a proof-of-concept for their further exploitation in antimicrobial strategies.

George P C Salmond - One of the best experts on this subject based on the ideXlab platform.

  • The bacterial Type III toxin-Antitoxin system, ToxIN, is a dynamic protein-RNA complex with stability-dependent antiviral abortive infection activity
    Nature Publishing Group, 2018
    Co-Authors: Francesca L Short, Chidiebere Akusobi, William R. Broadhurst, George P C Salmond
    Abstract:

    Abstract Bacteria have evolved numerous defense systems to protect themselves from viral (bacteriophage) infection. The ToxIN system of Pectobacterium atrosepticum is a Type III toxin-Antitoxin complex and “altruistic suicide” anti-phage system, which kills phage-infected cells through the release of a ribonuclease toxin, ToxN. ToxN is counteracted by a co-transcribed antitoxic RNA pseudoknot, ToxI, which self-assembles with ToxN into an inactive 3 ToxI:3 ToxN complex in vitro. However it is not known whether this complex is predominant in vivo, or how the complex is disassembled following infection to trigger a lethal, “altruistic” response. In this study, we characterise ToxI turnover and folding, and explore the link between complex stability and anti-phage activity, with a view to understanding events that lead to ToxN-mediated suicide following phage infection. We present evidence that ToxN constantly cleaves fresh ToxI in vivo rather than staying associated with pre-processed Antitoxin, and that the ToxI Antitoxin can partially fold spontaneously using conserved nucleotides. We also show that reducing the stability of the ToxIN complex can increase the strength of the antiviral response in a phage-dependent manner. Based on this information, we propose a revised model for ToxN inhibition, complex assembly and activation by infecting bacteriophage

  • selectivity and self assembly in the control of a bacterial toxin by an antitoxic noncoding rna pseudoknot
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Francesca L Short, Tim R Blower, Ben F Luisi, Peter C. Fineran, Xue Y Pei, Shue Li Ong, George P C Salmond
    Abstract:

    Bacterial small RNAs perform numerous regulatory roles, including acting as antitoxic components in toxin–Antitoxin systems. In type III toxin–Antitoxin systems, small processed RNAs directly antagonize their toxin protein partners, and in the systems characterized the toxin and Antitoxin components together form a trimeric assembly. In the present study, we sought to define how the RNA Antitoxin, ToxI, inhibits its potentially lethal protein partner, ToxN. We show through cross-inhibition experiments with the ToxIN systems from Pectobacterium atrosepticum (ToxINPa) and Bacillus thuringiensis (ToxINBt) that ToxI RNAs are highly selective enzyme inhibitors. Both systems have an “addictive” plasmid maintenance phenotype. We demonstrate that ToxIPa can inhibit ToxNPa in vitro both in its processed form and as a repetitive precursor RNA, and this inhibition is linked to the self-assembly of the trimeric complex. Inhibition and self-assembly are both mediated entirely by the ToxIPa RNA, with no requirement for cellular factors or exogenous energy. Finally, we explain the origins of ToxI Antitoxin selectivity through our crystal structure of the ToxINBt complex. Our results show how a processed RNA pseudoknot can inhibit a deleterious protein with exquisite molecular specificity and how these self-contained and addictive RNA-protein pairs can confer different adaptive benefits in their bacterial hosts.

  • identification and classification of bacterial type iii toxin Antitoxin systems encoded in chromosomal and plasmid genomes
    Nucleic Acids Research, 2012
    Co-Authors: Tim R Blower, Ben F Luisi, Peter C. Fineran, Francesca L Short, Xue Y Pei, Feng Rao, Kenji Mizuguchi, George P C Salmond
    Abstract:

    Toxin–Antitoxin systems are widespread in bacteria and archaea. They perform diverse functional roles, including the generation of persistence, maintenance of genetic loci and resistance to bacteriophages through abortive infection. Toxin–Antitoxin systems have been divided into three types, depending on the nature of the interacting macromolecules. The recently discovered Type III toxin–Antitoxin systems encode protein toxins that are inhibited by pseudoknots of antitoxic RNA, encoded by short tandem repeats upstream of the toxin gene. Recent studies have identified the range of Type I and Type II systems within current sequence databases. Here, structure-based homology searches were combined with iterative protein sequence comparisons to obtain a current picture of the prevalence of Type III systems. Three independent Type III families were identified, according to toxin sequence similarity. The three families were found to be far more abundant and widespread than previously known, with examples throughout the Firmicutes, Fusobacteria and Proteobacteria. Functional assays confirmed that representatives from all three families act as toxin–Antitoxin loci within Escherichia coli and at least two of the families confer resistance to bacteriophages. This study shows that active Type III toxin–Antitoxin systems are far more diverse than previously known, and suggests that more remain to be identified.

  • balancing at survival s edge the structure and adaptive benefits of prokaryotic toxin Antitoxin partners
    Current Opinion in Structural Biology, 2011
    Co-Authors: Tim R Blower, George P C Salmond, Ben F Luisi
    Abstract:

    Many prokaryotes express toxin-Antitoxin (TA) pairs that are harmful to their hosts if not maintained in delicate balance. The maintenance of potentially lethal toxin-Antitoxin pairs could be viewed as a high-risk strategy. However, accumulating evidence suggests that toxin-Antitoxin pairs can confer selective evolutionary benefits such as adaptive stress responses, starvation recovery and herd immunity to predation. Many of the known TA pairs interact as proteins, but recent work has identified a new class of Antitoxins that are RNA cleavage products. Structural studies have revealed common folds for diverse toxins, highlighting unexpected evolutionary relationships within different toxin classes. TA pairs appear to have diverged in function considerably, to meet the specialised requirements of their varied prokaryotic hosts.