Type II Toxin-Antitoxin Loci: The Epsilon/zeta Family

Mutschler, Hannes; Meinhart, Anton

doi:10.1007/978-3-642-33253-1_12

Cited by 7 publications

(16 citation statements)

References 63 publications

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“…The paaR-paaA-parE operon is co-transcribed from a σ 70 -type promoter upstream of paaR (Hallez et al, 2010 ). Unlike the ω-ε-ζ system in which ε-ζ did not play any role in transcriptional regulation (Mutschler and Meinhart, 2013 ), the PaaA antitoxin forms a complex with the ParE toxin that repress transcription from the paaR promoter, albeit partially. Full repression of transcription requires the PaaR regulator (Hallez et al, 2010 ).…”

Section: Tripartite Type II Ta Locimentioning

confidence: 99%

“…In this instance, no homologs of the ω regulator is evident in the S. pneumoniae genome (Khoo et al, 2007 ) and it is clear that ω and the repressor domain of PezA have different evolutionary origins. It was postulated that pezA likely originated from a fusion event of an unrelated transcriptional repressor coding sequence to the 5′-end of the coding sequence of an ε ortholog (Mutschler and Meinhart, 2013 ). Hints of involvement of PezAT in the pathogenicity of S. pneumoniae and its function in the pneumococcal pathogenicity island 1 (Brown et al, 2004 ; Harvey et al, 2011 ; Mutschler and Meinhart, 2011 ; Chan et al, 2012 ) as well as a pneumococcal integrative and conjugative element (ICE; Chan et al, 2014 ; Iannelli et al, 2014 ) warrants further investigations.…”

Section: Caveats: the Ezet And Vapc-1 Toxinsmentioning

confidence: 99%

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Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Chan

Espinosa

Yeo

2016

Front. Mol. Biosci.

129

121

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In their initial stages of discovery, prokaryotic toxin-antitoxin (TA) systems were confined to bacterial plasmids where they function to mediate the maintenance and stability of usually low- to medium-copy number plasmids through the post-segregational killing of any plasmid-free daughter cells that developed. Their eventual discovery as nearly ubiquitous and repetitive elements in bacterial chromosomes led to a wealth of knowledge and scientific debate as to their diversity and functionality in the prokaryotic lifestyle. Currently categorized into six different types designated types I–VI, type II TA systems are the best characterized. These generally comprised of two genes encoding a proteic toxin and its corresponding proteic antitoxin, respectively. Under normal growth conditions, the stable toxin is prevented from exerting its lethal effect through tight binding with the less stable antitoxin partner, forming a non-lethal TA protein complex. Besides binding with its cognate toxin, the antitoxin also plays a role in regulating the expression of the type II TA operon by binding to the operator site, thereby repressing transcription from the TA promoter. In most cases, full repression is observed in the presence of the TA complex as binding of the toxin enhances the DNA binding capability of the antitoxin. TA systems have been implicated in a gamut of prokaryotic cellular functions such as being mediators of programmed cell death as well as persistence or dormancy, biofilm formation, as defensive weapons against bacteriophage infections and as virulence factors in pathogenic bacteria. It is thus apparent that these antitoxins, as DNA-binding proteins, play an essential role in modulating the prokaryotic lifestyle whilst at the same time preventing the lethal action of the toxins under normal growth conditions, i.e., keeping the proverbial wolves at bay. In this review, we will cover the diversity and characteristics of various type II TA antitoxins. We shall also look into some interesting deviations from the canonical type II TA systems such as tripartite TA systems where the regulatory role is played by a third party protein and not the antitoxin, and a unique TA system encoding a single protein with both toxin as well as antitoxin domains.

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Section: Tripartite Type II Ta Locimentioning

confidence: 99%

Section: Caveats: the Ezet And Vapc-1 Toxinsmentioning

confidence: 99%

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Chan

Espinosa

Yeo

2016

Front. Mol. Biosci.

129

121

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“…The type II toxins use different strategies to regulate growth control and cellular processes related to the general stress response. Toxins of the ζ/PezT superfamily, which are among the most broadly distributed in nature, are found in major human pathogens and in environmentally important bacteria of the phylum Firmicutes (Mutschler and Meinhart, 2013 ). The plasmid-borne ζ gene product from Streptococcus pyogenes, Streptococcus agalactiae or Enterococcus faecalis and the chromosome-encoded ζ toxin from Clostridium perfringens or Staphylococcus aureus (~285 amino acids) share ~43% sequence identity with chromosome-encoded Streptococcus pneumoniae or Streptococcus suis PezT toxin (~255 amino acids) (reviewed in Mutschler and Meinhart, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Toxin ζ Triggers a Survival Response to Cope with Stress and Persistence

et al. 2017

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Bacteria have evolved complex regulatory controls in response to various environmental stresses. Protein toxins of the ζ superfamily, found in prominent human pathogens, are broadly distributed in nature. We show that ζ is a uridine diphosphate-N-acetylglucosamine (UNAG)-dependent ATPase whose activity is inhibited in vitro by stoichiometric concentrations of ε2 antitoxin. In vivo, transient ζ expression promotes a reversible multi-level response by altering the pool of signaling purine nucleotides, which leads to growth arrest (dormancy), although a small cell subpopulation persists rather than tolerating toxin action. High c-di-AMP levels (absence of phosphodiesterase GdpP) decrease, and low c-di-AMP levels (absence of diadenylate cyclase DisA) increase the rate of ζ persistence. The absence of CodY, a transition regulator from exponential to stationary phase, sensitizes cells to toxin action, and suppresses persisters formed in the ΔdisA context. These changes, which do not affect the levels of stochastic ampicillin (Amp) persistence, sensitize cells to toxin and Amp action. Our findings provide an explanation for the connection between ζ-mediated growth arrest (with alterations in the GTP and c-di-AMP pools) and persistence formation.

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“…Whether the product of this plasmid-encoded xerC-like gene or the chromosomally-encoded XerCD are involved in the mobility of the pdif modules will require future experimental validation.The plasmid-encoded xerC-like gene is divergently transcribed from a gene encoding a Zeta-like toxin which is interrupted by ISAba11 in pAC1530. This putative Zeta-like toxin, at 501 aa residues, is much larger than canonical Zeta toxins (~270 aa) of the Epsilon-Zeta/PezAT TA systems(63,64) and is even larger than the 360 aa Zetalike toxins of several Acinetobacter plasmids that had been previously characterized as "non-functional" toxins(65). There was conservation of amino acid residues within the Walker A motif of Zeta toxins which function to bind ATP for phosphorylation reactions but no conservation of amino acids that bind to the substrate for Zeta, UDP-Nacetylglucosamine (UNAG) (63) was observed for the pAC1633-1-encoded Zeta.…”

mentioning

confidence: 88%

Complete genome sequencing ofAcinetobacter baumanniiAC1633 andAcinetobacter nosocomialisAC1530 unveils a large multidrug resistant plasmid encoding the NDM-1 and OXA-58 carbapenemases

Alattraqchi

Rani

Rahman

et al. 2020

Preprint

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Carbapenem-resistant Acinetobacter spp. are considered priority drug-resistant human pathogenic bacteria. The genomes of two carbapenem-resistant Acinetobacter spp. clinical isolates obtained from the same tertiary hospital in Terengganu, Malaysia, namely A. baumannii AC1633 and A. nosocomialis AC1530, were sequenced. Both isolates were found to harbor the carbapenemase genes blaNDM-1 and blaOXA-58 in a large (ca. 170 kb) plasmid designated pAC1633-1 and pAC1530, respectively, that also encodes genes that confer resistance to aminoglycosides, sulfonamides, and macrolides. The two plasmids were almost identical except for the insertion of ISAba11 and an IS4 family element in pAC1633-1, and ISAba11 along with relBE toxin-antitoxin genes flanked by inversely orientated pdif (XerC/XerD) recombination sites in pAC1530. The blaNDM-1 gene was encoded in a Tn125 composite transposon structure flanked by ISAba125 whereas blaOXA-58 was flanked by ISAba11 and ISAba3 downstream and a partial ISAba3 element upstream within a pdif module. The presence of conjugative genes in plasmids pAC1633-1/pAC1530 and their discovery in two distinct species of Acinetobacter from the same hospital are suggestive of conjugative transfer but mating experiments failed to demonstrate transmissibility under standard laboratory conditions. Comparative sequence analysis strongly inferred that pAC1633-1/pAC1530 was derived from two separate plasmids in an IS1006-mediated recombination or transposition event. A. baumannii AC1633 also harbored three other plasmids designated pAC1633-2, pAC1633-3 and pAC1633-4. Both pAC1633-3 and pAC1633-4 are cryptic plasmids whereas pAC1633-2 is a 12,651 bp plasmid of the GR8/GR23 Rep3-superfamily group that encodes the tetA(39) tetracycline resistance determinant in a pdif module.

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Type II Toxin-Antitoxin Loci: The Epsilon/zeta Family

Cited by 7 publications

References 63 publications

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Toxin ζ Triggers a Survival Response to Cope with Stress and Persistence

Complete genome sequencing ofAcinetobacter baumanniiAC1633 andAcinetobacter nosocomialisAC1530 unveils a large multidrug resistant plasmid encoding the NDM-1 and OXA-58 carbapenemases

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