Induced ectopic expression of <scp>HigB</scp> toxin in <i><scp>M</scp>ycobacterium tuberculosis</i> results in growth inhibition, reduced abundance of a subset of <scp>mRNAs</scp> and cleavage of <scp>tmRNA</scp>

Schuessler, Dorothée L.; Cortes, Teresa; Fivian‐Hughes, Amanda S.; Lougheed, Kathryn; Harvey, Evelyn; Buxton, Roger S.; Davis, E. A.; Young, Douglas B.

doi:10.1111/mmi.12358

Cited by 51 publications

(44 citation statements)

References 76 publications

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“…This is consistent with our previous results, in which we have shown that two other TA loci toxins in NTHi, VapC-1 and VapD, are active on free RNA in vitro [13], [23]. Other studies have found that induced ectopic expression of the HigB toxin in M. tuberculosis lead to growth arrest and cell death as well as cleavage of tmRNA and mRNA predominantly from genes regulated by the IdeR iron-dependent repressor and the zinc uptake repressor Zur [24]. However, the HigB cleavage sites identified in the M. tuberculosis tmRNA ssrA in that investigation were not particularly A-rich.…”

Section: Resultssupporting

confidence: 93%

The ToxAvapA Toxin-Antitoxin Locus Contributes to the Survival of Nontypeable Haemophilus influenzae during Infection

et al. 2014

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Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen that is a common cause of acute and recurrent mucosal infections. One uncharacterized NTHi toxin-antitoxin (TA) module, NTHI1912-1913, is a host inhibition of growth (higBA) homologue. We hypothesized that this locus, which we designated toxAvapA, contributed to NTHi survival during infection. We deleted toxAvapA and determined that growth of the mutant in defined media was not different from the parent strain. We tested the mutant for persistence during long-term in vitro co-culture with primary human respiratory tissues, which revealed that the ΔtoxAvapA mutant was attenuated for survival. We then performed challenge studies using the chinchilla model of otitis media and determined that mutant survival was also reduced in vivo. Following purification, the toxin exhibited ribonuclease activity on RNA in vitro, while the antitoxin did not. A microarray comparison of the transcriptome revealed that the tryptophan biosynthetic regulon was significantly repressed in the mutant compared to the parent strain. HPLC studies of conditioned medium confirmed that there was no significant difference in the concentration of tryptophan remaining in the supernatant, indicating that the uptake of tryptophan by the mutant was not affected. We conclude that the role of the NTHi toxAvapA TA module in persistence following stress is multifactorial and includes effects on essential metabolic pathways.

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Section: Resultssupporting

confidence: 93%

The ToxAvapA Toxin-Antitoxin Locus Contributes to the Survival of Nontypeable Haemophilus influenzae during Infection

et al. 2014

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“…We revealed an 87‐amino acid‐long conserved domain of a putative HigB‐like addiction module killer toxin ( e ‐value < 10 −10 ) (Schuessler et al . ). A 222‐amino acid‐long putative transcriptional regulator of the xenobiotic response element family, which might serve as an antitoxin protein, was found downstream and antisense to the toxin ( e ‐value < 10 −8 ).…”

Section: Resultsmentioning

confidence: 97%

Adaptation of genetically monomorphic bacteria: evolution of copper resistance through multiple horizontal gene transfers of complex and versatile mobile genetic elements

et al. 2017

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Copper-based antimicrobial compounds are widely used to control plant bacterial pathogens. Pathogens have adapted in response to this selective pressure. Xanthomonas citri pv. citri, a major citrus pathogen causing Asiatic citrus canker, was first reported to carry plasmid-encoded copper resistance in Argentina. This phenotype was conferred by the copLAB gene system. The emergence of resistant strains has since been reported in Réunion and Martinique. Using microsatellite-based genotyping and copLAB PCR, we demonstrated that the genetic structure of the copper-resistant strains from these three regions was made up of two distant clusters and varied for the detection of copLAB amplicons. In order to investigate this pattern more closely, we sequenced six copper-resistant X. citri pv. citri strains from Argentina, Martinique and Réunion, together with reference copper-resistant Xanthomonas and Stenotrophomonas strains using long-read sequencing technology. Genes involved in copper resistance were found to be strain dependent with the novel identification in X. citri pv. citri of copABCD and a cus heavy metal efflux resistance-nodulation-division system. The genes providing the adaptive trait were part of a mobile genetic element similar to Tn3-like transposons and included in a conjugative plasmid. This indicates the system's great versatility. The mining of all available bacterial genomes suggested that, within the bacterial community, the spread of copper resistance associated with mobile elements and their plasmid environments was primarily restricted to the Xanthomonadaceae family.

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“…Transcription of TAC is induced in host phagocytes and by several stresses relevant for M. tuberculosis , including DNA damage, heat shock, nutrient starvation, hypoxia and multidrug persistence1013. In addition, ectopic expression of the Mtb -HigB1 toxin severely inhibits M. tuberculosis , M. marinum , M. smegmatis and Escherichia coli growth131415, and affects the relative abundance of over 30 transcripts in M. tuberculosis 15.…”

mentioning

confidence: 99%

Chaperone addiction of toxin–antitoxin systems

et al. 2016

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Bacterial toxin–antitoxin (TA) systems, in which a labile antitoxin binds and inhibits the toxin, can promote adaptation and persistence by modulating bacterial growth in response to stress. Some atypical TA systems, known as tripartite toxin–antitoxin–chaperone (TAC) modules, include a molecular chaperone that facilitates folding and protects the antitoxin from degradation. Here we use a TAC module from Mycobacterium tuberculosis as a model to investigate the molecular mechanisms by which classical TAs can become ‘chaperone-addicted'. The chaperone specifically binds the antitoxin at a short carboxy-terminal sequence (chaperone addiction sequence, ChAD) that is not present in chaperone-independent antitoxins. In the absence of chaperone, the ChAD sequence destabilizes the antitoxin, thus preventing toxin inhibition. Chaperone–ChAD pairs can be transferred to classical TA systems or to unrelated proteins and render them chaperone-dependent. This mechanism might be used to optimize the expression and folding of heterologous proteins in bacterial hosts for biotechnological or medical purposes.

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Induced ectopic expression of HigB toxin in Mycobacterium tuberculosis results in growth inhibition, reduced abundance of a subset of mRNAs and cleavage of tmRNA

Cited by 51 publications

References 76 publications

The ToxAvapA Toxin-Antitoxin Locus Contributes to the Survival of Nontypeable Haemophilus influenzae during Infection

The ToxAvapA Toxin-Antitoxin Locus Contributes to the Survival of Nontypeable Haemophilus influenzae during Infection

Adaptation of genetically monomorphic bacteria: evolution of copper resistance through multiple horizontal gene transfers of complex and versatile mobile genetic elements

Chaperone addiction of toxin–antitoxin systems

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