Transcriptional cross-activation between toxin-antitoxin systems of Escherichia coli

Kasari, Villu; Mets, Toomas; Tenson, Tanel; Kaldalu, Niilo

doi:10.1186/1471-2180-13-45

Cited by 64 publications

(72 citation statements)

References 74 publications

(91 reference statements)

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“…12,45,55,56 Recent studies have demonstrated that TA-II systems can affect positively or negatively the expression of other TA-II modules. 39,57,58 However in these studies, only changes in steady-state RNA levels have been shown, and RNA synthesis (transcription) and RNA stability effects cannot be distinguished. In our experiments, direct RNA stability measurements rule out stability effects of MazE and MazEF on RatA, since the RatA half-life is independent of MazE and MazEF levels.…”

Section: Discussionmentioning

confidence: 99%

“…For instance in E. coli, the TA-II endoribonuclease toxin MsqR was shown to enhance a selective degradation of the ghoST mRNA in favor of the type V TA toxin GhoT, by direct cleavage within the ghoS sequence and, a complex regulatory interplay has been unveiled between several TA-II modules. 38,39 These observations suggest that together TAs may mediate concerted physiological responses in the cell.…”

Section: Introductionmentioning

confidence: 93%

“…A few reports show that TA-II modules coordinate their expression by acting on their respective RNA levels or by direct interactions between non-cognate toxins and antitoxins. 39,58 Modeling such interactions suggests that interplays between TAs offer better chances to create heterogeneous populations. 59 Thus, it is tempting to speculate that functional and regulatory crosstalks between TAs, associated to genomic plasticity may provide the E. faecalis species with capacities to conquer habitats and adapt life styles.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

et al. 2015

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We discovered a chromosomal locus containing 2 toxin-antitoxin modules (TAs) with an antisense transcriptional organization in the E. faecalis clinical isolate V583. These TAs are homologous to the type I txpA-ratA system and the type II mazEF, respectively. We have shown that the putative MazF is toxic for E. coli and triggers RNA degradation, and its cognate antitoxin MazE counteracts toxicity. The second module, adjacent to mazEF, expresses a toxin predicted to belong to the TxpA type I family found in Firmicutes, and the antisense RNA antidote, RatA. Genomic analysis indicates that the cis-association of mazEF and txpA-ratA modules has been favored during evolution, suggesting a selective advantage for this TA organization in the E. faecalis species. We showed regulatory interplays between the 2 modules, involving transcription control and RNA stability. Remarkably, our data reveal that MazE and MazEF have a dual transcriptional activity: they act as autorepressors and activate ratA transcription, most likely in a direct manner. RatA controls txpA RNA levels through stability. Our data suggest a pivotal role of MazEF in the coordinated expression of mazEF and txpA-ratA modules in V583. To our knowledge, this is the first report describing a crosstalk between type I and II TAs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

et al. 2015

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“…HipA activity triggers ppGpp, which may then induce the development of persistence through the activation of other toxins which do not rely upon the maintenance of high ppGpp for antibiotic tolerance. It was recently shown that overexpression of HipA triggers the transcriptional activation of other TA modules (54).…”

Section: Discussionmentioning

confidence: 99%

HipA-Triggered Growth Arrest and -Lactam Tolerance in Escherichia coli Are Mediated by RelA-Dependent ppGpp Synthesis

Bokinsky¹,

Baidoo²,

Akella³

et al. 2013

Journal of Bacteriology

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Persistence is a phenomenon whereby a subpopulation of bacterial cells enters a transient growth-arrested state that confers antibiotic tolerance. While entrance into persistence has been linked to the activities of toxin proteins, the molecular mechanisms by which toxins induce growth arrest and the persistent state remain unclear. Here, we show that overexpression of the protein kinase HipA in Escherichia coli triggers growth arrest by activating synthesis of the alarmone guanosine tetraphosphate (ppGpp) by the enzyme RelA, a signal typically associated with amino acid starvation. We further demonstrate that chemically suppressing ppGpp synthesis with chloramphenicol relieves inhibition of DNA replication initiation and RNA synthesis in HipA-arrested cells and restores vulnerability to ␤-lactam antibiotics. HipA-arrested cells maintain glucose uptake and oxygen consumption and accumulate amino acids as a consequence of translational inhibition. We harness the active metabolism of HipA-arrested cells to provide a bacteriophage-resistant platform for the production of biotechnologically relevant compounds, which may represent an innovative solution to the costly problem of phage contamination in industrial fermentations.

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“…However, the effect of TA systems on bacterial fitness can be seen when multiple TA loci have been deleted from the chromosome, indicating that chromosomal TA systems constitute a redundant network (21). As shown recently, the coordinated activation of the TA network in E. coli involves increased activity of the Lon protease that is triggered by the stringent response (15,23). Transcriptional cross-activation between different TA systems has also been suggested as a mechanism for a synchronized response (23).…”

mentioning

confidence: 99%

Stability of the GraA Antitoxin Depends on Growth Phase, ATP Level, and Global Regulator MexT

et al. 2016

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Bacterial type II toxin-antitoxin systems consist of a potentially poisonous toxin and an antitoxin that inactivates the toxic protein by binding to it. Most of the toxins regulate stress survival, but their activation depends on the stability of the antitoxin that has to be degraded in order for the toxin to be able to attack its cellular targets. The degradation of antitoxins is usually rapid and carried out by ATP-dependent protease Lon or Clp, which is activated under stress conditions. The graTA system of Pseudomonas putida encodes the toxin GraT, which can affect the growth rate and stress tolerance of bacteria but is under most conditions inactivated by the unusually stable antitoxin GraA. Here, we aimed to describe the stability features of the antitoxin GraA by analyzing its degradation rate in total cell lysates of P. putida. We show that the degradation rate of GraA depends on the growth phase of bacteria being fastest in the transition from exponential to stationary phase. In accordance with this, higher ATP levels were shown to stabilize GraA. Differently from other antitoxins, the main cellular proteases Lon and Clp are not involved in GraA stability. Instead, GraA seems to be degraded through a unique pathway involving an endoprotease that cleaves the antitoxin into two unequal parts. We also identified the global transcriptional regulator MexT as a factor for destabilization of GraA, which indicates that the degradation of GraA may be induced by conditions similar to those that activate MexT. IMPORTANCEToxin-antitoxin (TA) modules are widespread in bacterial chromosomes and have important roles in stress tolerance. As activation of a type II toxin is triggered by proteolytic degradation of the antitoxin, knowledge about the regulation of the antitoxin stability is critical for understanding the activation of a particular TA module. Here, we report on the unusual degradation pathway of the antitoxin GraA of the recently characterized GraTA system. While GraA is uncommonly stable in the exponential and late-stationary phases, its degradation increases in the transition phase. The degradation pathway of GraA involves neither Lon nor Clp, which usually targets antitoxins, but rather an unknown endoprotease and the global regulator MexT, suggesting a new type of regulation of antitoxin stability.

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Transcriptional cross-activation between toxin-antitoxin systems of Escherichia coli

Cited by 64 publications

References 74 publications

Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

HipA-Triggered Growth Arrest and -Lactam Tolerance in Escherichia coli Are Mediated by RelA-Dependent ppGpp Synthesis

Stability of the GraA Antitoxin Depends on Growth Phase, ATP Level, and Global Regulator MexT

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