The Escherichia coli Toxin MqsR Destabilizes the Transcriptional Repression Complex Formed between the Antitoxin MqsA and the mqsRA Operon Promoter

Brown, Breann L.; Lord, Dana M.; Grigoriu, Simina; Peti, Wolfgang; Page, Rebecca

doi:10.1074/jbc.m112.421008

Cited by 78 publications

(89 citation statements)

References 50 publications

(56 reference statements)

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“…Thus, our data do not support GraT-mediated corepression, and we conclude that the graTA operon is autorepressed by GraA only. Therefore, graTA regulation seems to resemble that of the mqsRA operon, as recent data demonstrate that the MqsR toxin is not a corepressor but rather alleviates MqsA-mediated repression (57).…”

Section: Discussionmentioning

confidence: 94%

“…It is common in type II TA systems that their operons are autorepressed by either the antitoxin or the toxin-antitoxin complex (52,57,58). In the latter case, the antitoxin is the DNAbinding moiety and the toxin acts as a corepressor if the ratio of toxin to antitoxin is low or as a derepressor if toxin is in excess (59,60).…”

Section: Discussionmentioning

confidence: 99%

“…Transcriptional coregulation of TA operons by toxin abundance is common among TA systems and is known as conditional cooperativity (61)(62)(63). However, TA operons can also be regulated by other mechanisms involving promoter repression by antitoxin alone or even activation by antitoxin (18,57). Similarly to most TA systems, the graTA operon is regulated by autorepression (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A Moderate Toxin, GraT, Modulates Growth Rate and Stress Tolerance of Pseudomonas putida

Tamman¹,

Ainelo²,

Ainsaar³

et al. 2013

Journal of Bacteriology

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Chromosomal toxin-antitoxin (TA) systems are widespread among free-living bacteria and are supposedly involved in stress tolerance. Here, we report the first TA system identified in the soil bacterium Pseudomonas putida. The system, encoded by the loci PP1586-PP1585, is conserved in pseudomonads and belongs to the HigBA family. The new TA pair was named GraTA for the growth rate-affecting ability of GraT and the antidote activity of GraA. The GraTA system shares many features common to previously described type II TA systems. The overexpression of GraT is toxic to the antitoxin deletion mutants, since the toxin's neutralization is achieved by binding of the antitoxin. Also, the graTA operon structure and autoregulation by antitoxin resemble those of other TA loci. However, we were able to delete the antitoxin gene from the chromosome, which shows the unusually mild toxicity of innate GraT compared to previously described toxins. Furthermore, GraT is a temperature-dependent toxin, as its growth-regulating effect becomes more evident at lower temperatures. Besides affecting the growth rate, GraT also increases membrane permeability, resulting in higher sensitivity to some chemicals, e.g., NaCl and paraquat. Nevertheless, the active toxin helps the bacteria survive under different stressful conditions and increases their tolerance to several antibiotics, including streptomycin, kanamycin, and ciprofloxacin. Therefore, our data suggest that GraT may represent a new class of mild chromosomal regulatory toxins that have evolved to be less harmful to their host bacterium. Their moderate toxicity might allow finer growth and metabolism regulation than is possible with strong growth-arresting or bactericidal toxins.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Moderate Toxin, GraT, Modulates Growth Rate and Stress Tolerance of Pseudomonas putida

Tamman¹,

Ainelo²,

Ainsaar³

et al. 2013

Journal of Bacteriology

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“…This "conditional cooperativity" mechanism relies on allosteric modification of the antitoxin upon toxin binding (43,44). In contrast to canonical type II TASs, the dimeric E. coli MqsA antitoxin (a member of the HTH repressor family) does not exhibit conditional cooperativity (45). MqsA is fully folded and binds DNA alone.…”

Section: Discussionmentioning

confidence: 99%

Functional and Structural Analysis of HicA3-HicB3, a Novel Toxin-Antitoxin System of Yersinia pestis

et al. 2014

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The mechanisms involved in the virulence of Yersinia pestis, the plague pathogen, are not fully understood. In previous research, we found that a Y. pestis mutant lacking the HicB3 (YPO3369) putative orphan antitoxin was attenuated for virulence in a murine model of bubonic plague. Toxin-antitoxin systems (TASs) are widespread in prokaryotes. Most bacterial species possess many TASs of several types. In type II TASs, the toxin protein is bound and neutralized by its cognate antitoxin protein in the cytoplasm. Here we identify the hicA3 gene encoding the toxin neutralized by HicB3 and show that HicA3-HicB3 constitutes a new functional type II TAS in Y. pestis. Using biochemical and mutagenesis-based approaches, we demonstrate that the HicA3 toxin is an RNase with a catalytic histidine residue. HicB3 has two functions: it sequesters and neutralizes HicA3 by blocking its active site, and it represses transcription of the hicA3B3 operon. Gel shift assays and reporter fusion experiments indicate that the HicB3 antitoxin binds to two operators in the hicA3B3 promoter region. We solved the X-ray structures of HicB3 and the HicA3-HicB3 complex; thus, we present the first crystal structure of a TA complex from the HicAB family. HicB3 forms a tetramer that can bind two HicA3 toxin molecules. HicA3 is monomeric and folds as a double-stranded-RNA-binding domain. The HicB3 N-terminal domain occludes the HicA3 active site, whereas its C-terminal domain folds as a ribbon-helix-helix DNAbinding motif.

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“…For example, the binding of MqsR toxin to MqsA causes the complex to fall off DNA since the binding sites of MqsA to DNA and to MqsR overlap, so MqsA cannot bind both its promoter and toxin. Hence, the regulation of mqsRA is not governed by conditional cooperativity (Brown, et al, 2013). Similarly, the E. coli…”

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confidence: 99%

Post-Segregational Killing, Altruistic Cell Death, and Other Toxin/Antitoxin Fallacies

Song¹,

Wood²

2018

Preprint

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The toxin/antitoxin (TA) field, born of controversy, is plagued by several prevailing misperceptions.For example, some TA systems stabilize plasmids and other genomic regions; however, the evidence of post-segregational killing by toxins of TA systems is weak. In addition, there are few credible reports of cell death via TA systems like MazF/MazE and via phage exclusion systems. Although many aspects of 5 the biological roles of TA systems remain enigmatic, there are now some clear, confirmed TA functions:(i) phage inhibition, (ii) plasmid maintenance, (iii) stress response (including regulation of loci distinct from the TA pair itself), (iv) biofilm formation, and (v) persistence. Therefore, this opinion piece aims to challenge the oft-repeated dogma related to TA systems with the goal of emphasizing their primary biological role: constraining metabolism in a reversible manner. Hence, their roles in their five confirmed 10 functions all stem from their ability to rapidly and reversibly reduce metabolic activity. REVIEWWe recently elucidated several misperceptions in a field related to toxin/antitoxin (TA) systems, persister cell biology Wood, 2016, 2017). Here, in the following sections, we aim to initiate a similar discussion about several dubious yet entrenched theories that are related to TA systems. Most of 15 these misperceptions are based on overproducing toxins; i.e., many toxins of TA systems appear lethal if produced from a strong promoter. However, conclusions based on overproducing proteins are seldom relevant for physiological conditions. Nebulous nomenclature. Historically, TA systems were deemed cytosolic (not secreted); hence, TA system toxins were considered primarily to affect the metabolism of the host that produced it rather than 20 as serving as a weapon against other cells, such as colicins (Rendueles, et al., 2014). With a better understanding of their biological function, growth diminution as opposed to cell death, TA systems would be more aptly named "growth inhibitors" and "silencers of growth inhibitors," rather than "toxins," which imply a poison used against competitors rather than an internal means to reduce metabolism. However, little would be served, and much confusion would ensue, if the name of the field was changed now. 25Moreover, TA system components have now starting to be found outside the cell. For example, the Song and Wood 3 type VII secretion system DNase toxin EsaD of the EsaD/EsaG TA system of Staphylococcus aureus (Cao, et al., 2016) is secreted for bacterial competitiveness; this is the second known toxin that is a DNase with RalR of the E. coli RalR/RalA TA system being the first (Guo, et al., 2014). The Xanthomonas oryzae type III secretion system toxin AvrRxo1 of the AvrRxo1/Arc1 TA system is also secreted into 30 plants and modifies nicotinamide adenine dinucleotide. Additionally, antitoxin MqsA of the MqsR/MqsA TA system of Xylella fastidiosa (Santiago, et al., 2016) is secreted via outer membrane vesicles.Therefore, the distinction between external to...

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The Escherichia coli Toxin MqsR Destabilizes the Transcriptional Repression Complex Formed between the Antitoxin MqsA and the mqsRA Operon Promoter

Cited by 78 publications

References 50 publications

A Moderate Toxin, GraT, Modulates Growth Rate and Stress Tolerance of Pseudomonas putida

A Moderate Toxin, GraT, Modulates Growth Rate and Stress Tolerance of Pseudomonas putida

Functional and Structural Analysis of HicA3-HicB3, a Novel Toxin-Antitoxin System of Yersinia pestis

Post-Segregational Killing, Altruistic Cell Death, and Other Toxin/Antitoxin Fallacies

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