Why so narrow: Distribution of anti-sense regulated, type I toxin-antitoxin systems compared with type II and type III systems

Coray, Dorien S.; Wheeler, Nicole E.; Heinemann, Jack A.; Gardner, Paul P.

doi:10.1080/15476286.2016.1272747

Cited by 30 publications

(21 citation statements)

References 51 publications

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“…This review will focus on type II systems. These elements are not only found in plasmids but also in other types of mobile genetic elements (such as phages and ICEs) as well as in chromosomes (see e.g., Anantharaman and Aravind, 2003;Pandey and Gerdes, 2005;Guglielmini and Van Melderen, 2011;Leplae et al, 2011;Ramisetty et al, 2016;Coray et al, 2017). While the roles of TAs, when located in mobile genetic elements, are reminiscent to that on plasmids, i.e., maintenance (Szekeres et al, 2007;Wozniak and Waldor, 2009;Huguet et al, 2016), the roles of chromosomally-encoded systems remains a largely debated topic in the field.…”

Section: Introductionmentioning

confidence: 99%

The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems

Jurėnas

Melderen

2020

Front. Genet.

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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.

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Section: Introductionmentioning

confidence: 99%

The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems

Jurėnas

Melderen

2020

Front. Genet.

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“…For other TA types, both the toxin and the antitoxin are proteins. In most studied type II TA systems, the proteinaceous antitoxin forms a complex with its cognate toxin leading to toxin inactivation 14 . Major functions of TA modules include plasmid maintenance, abortive phage infection and persister cell formation 15, 16, 17, 18, 19, 20 .…”

Section: Introductionmentioning

confidence: 99%

Type I toxin-antitoxin systems contribute to mobile genetic elements maintenance inClostridioides difficileand can be used as a counter-selectable marker for chromosomal manipulation

Peltier

Hamiot

Garneau

et al. 2020

Preprint

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Toxin-antitoxin (TA) systems are widespread on mobile genetic elements as well as in bacterial chromosomes. According to the nature of the antitoxin and its mode of action for toxin inhibition, TA systems are subdivided into different types. The first type I TA modules were recently identified in the human enteropathogen Clostridioides (formerly Clostridium) difficile. In type I TA, synthesis of the toxin protein is prevented by the transcription of an antitoxin RNA during normal growth. Here, we report the characterization of five additional type I TA systems present within phiCD630-1 and phiCD630-2 prophage regions of C. difficile 630. Toxin genes encode 34 to 47 amino acid peptides and their ectopic expression in C. difficile induces growth arrest. Growth is restored when the antitoxin RNAs, transcribed from the opposite strand, are co-expressed together with the toxin genes. In addition, we show that type I TA modules located within the phiCD630-1 prophage contribute to its stability and mediate phiCD630-1 heritability. Type I TA systems were found to be widespread in genomes of C. difficile phages, further suggesting their functional importance. We have made use of a toxin gene from one of type I TA modules of C. difficile as a counter-selectable marker to generate an efficient mutagenesis tool for this bacterium. This tool enabled us to delete all identified toxin genes within the phiCD630-1 prophage, thus allowing investigation of the role of TA in prophage maintenance. Furthermore, we were able to delete the large 49 kb phiCD630-2 prophage region using this improved procedure.

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“…Toxin–antitoxin (TA) proteins play a crucial role in generating persisters in several bacterial species( 20–22 ). These TA systems, known to modulate growth under various growth and stress conditions, are found in wide range of bacterial and archaeal chromosomes and plasmids ( 23–25 ). Research conducted during the past decade has clearly demonstrated that TA loci act as effectors of dormancy and persistence in several bacterial species ( 20, 21 ).…”

Section: Introductionmentioning

confidence: 99%

Host cholesterol dependent activation of VapC12 toxin enriches persister population duringMycobacterium tuberculosisinfection

Pandey

Talwar

Pandey

et al. 2019

Preprint

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32A worldwide increase in the frequency of multidrug-resistant and extensively drug-33 resistant cases of tuberculosis is mainly due to therapeutic noncompliance associated 34 with a lengthy treatment regimen. Depending on the drug susceptibility profile, the 35 treatment duration can extend from 6 months to 2 years. This protracted regimen is 36 attributed to a supposedly non-replicating and metabolically inert subset of the 37 Mycobacterium tuberculosis (Mtb) population, called 'persisters'. The mechanism 38 underlying stochastic generation and enrichment of persisters is not fully known. 39 We have previously reported that the utilization of host cholesterol is essential for 40 mycobacterial persistence. In this study, we have demonstrated that cholesterol-41 induced activation of a ribonuclease toxin (VapC12) inhibits translation by 42 targeting proT tRNA in Mtb. This results in cholesterol-specific growth modulation 43 that increases the frequency of the generation of persisters in a heterogeneous Mtb 44 population. Also, a null mutant strain of this toxin (ΔvapC12) failed to persist and 45 demonstrated an enhanced growth phenotype in a guinea pig model of Mtb 46 infection. Thus, we have identified a novel strategy through which cholesterol-47 specific activation of a toxin-antitoxin (TA) module in Mtb enhances persister 48 formation during infection. In addition to identifying the mechanism, the study 49 provides opportunity for targeting persisters, a new paradigm facilitating 50 tuberculosis drug development. 51 52 53 54 55 56 57 58 128the cholesterol-rich media. We have observed a decrease in the replication and metabolic 129 rates of wild-type (WT) H37Rv grown in the cholesterol-rich media by ten-and three-130 fold, respectively, compared with (WT) H37Rv grown in the glycerol-rich media ( Fig. 131 1A, 1B). An in-vitro time-kill curve assay revealed a cholesterol-specific increase in the 132 frequency of the generation of a rifamycin-tolerant sub-population (Fig. 1C). The TA loci 133 across bacterial species regulate growth (21,(29)(30)(31), therefore we speculated the 134 aforementioned phenotype to be regulated by one of the Mtb TA loci. For that we 135 analysed the data of a transposon mutagenesis screening performed in Mtb H37Rv to 136 identify genes essential for growth in a cholesterol-rich environment(32). Through 137

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Why so narrow: Distribution of anti-sense regulated, type I toxin-antitoxin systems compared with type II and type III systems

Cited by 30 publications

References 51 publications

The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems

The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems

Type I toxin-antitoxin systems contribute to mobile genetic elements maintenance inClostridioides difficileand can be used as a counter-selectable marker for chromosomal manipulation

Host cholesterol dependent activation of VapC12 toxin enriches persister population duringMycobacterium tuberculosisinfection

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