Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways

Muthuramalingam, Meenakumari; White, John; Bourne, Christina R.

doi:10.3390/toxins8070214

Cited by 89 publications

(82 citation statements)

References 163 publications

(216 reference statements)

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“…To determine the kinetics of these transcriptional responses, we subjected E. coli to two well-studied stresses, the stringent response to amino acid starvation, which can be rapidly induced via addition of serine hydroxamate (SHX), and translation inhibition, induced by treatment with chloramphenicol. Consistent with previous reports (Christensen-Dalsgaard et al, 2010;Muthuramalingam et al, 2016;Ronneau and Helaine, 2019;Shan et al, 2017), we found an increase of at least 6-fold in the mRNA levels of three type II TA systems in E. coli MG1655, mqsRA, relBE, and yefM-yoeB, at both 15 and 30 minutes after treatment using quantitative reverse transcription PCR (qRT-PCR) ( Fig. 1B-C).…”

Section: Type II Ta Systems Are Transcriptionally Induced By Diverse supporting

confidence: 92%

“…This model claimed that ppGpp promoted the accumulation of polyphosphate, which then directly stimulated Lon to degrade antitoxins, thereby liberating toxins to promote persistence. While results related to persistence were cited in a retraction of this paper, the data related to Lon activation were not and recent literature continues to invoke a connection between ppGpp and TA systems (Christensen-Dalsgaard et al, 2010;Muthuramalingam et al, 2016;Ronneau and Helaine, 2019). Thus, we wanted to test whether the stringent response and ppGpp are required for the transcriptional activation of TA systems.…”

Section: Transcriptional Induction Of Ta Systems Does Not Require Thementioning

confidence: 98%

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Stress induces the transcription of toxin-antitoxin systems but does not activate toxin

LeRoux

Culviner

Liu

et al. 2020

Preprint

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Toxin-antitoxin (TA) systems are ubiquitous genetic elements in bacterial genomes, but their functions are controversial. Although they are frequently postulated to regulate cell growth following stress, few null phenotypes for TA systems have been reported. Here, we show that TA transcript levels can increase substantially in response to stress, but toxin is not liberated. We find that the growth of an Escherichia coli strain lacking 10 TA systems encoding endoribonuclease toxins is not affected following exposure to six stresses that each trigger TA transcription.Additionally, using RNA-sequencing, we find no evidence of mRNA cleavage following stress.Stress-induced transcription arises from antitoxin degradation and relief of transcriptional autoregulation. Importantly, although free antitoxin is readily degraded in vivo, antitoxin bound to toxin is protected from proteolysis, preventing release of active toxin. Thus, transcription is not a reliable marker of TA activity, and TA systems likely do not strongly promote survival following stress.

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Section: Type II Ta Systems Are Transcriptionally Induced By Diverse supporting

confidence: 92%

Section: Transcriptional Induction Of Ta Systems Does Not Require Thementioning

confidence: 98%

Stress induces the transcription of toxin-antitoxin systems but does not activate toxin

LeRoux

Culviner

Liu

et al. 2020

Preprint

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“…Here, we examined if loss of toxins led to reduced induction of persistence following nutrient limitation or ROS, specifically NO. Indeed, we found that ΔBPSS0390 could not generate the same level of persisters after sNO exposure, whereas all three toxins had a significant reduction in persistence due to nutrient starvation (Kolodkin‐Gal, Verdiger, Shlosberg‐Fedida, & Engelberg‐Kulka, ; Muthuramalingam, White, & Bourne, ). However, further investigation is needed to determine the repertoire of stresses these toxins are responding to in macrophages.…”

Section: Discussionmentioning

confidence: 92%

Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection

Ross

Micheva-Viteva

Hong-Geller

et al. 2019

Cellular Microbiology

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Burkholderia pseudomallei is the causative agent of melioidosis, a disease with a mortality rate of up to 40% even with treatment. Despite the ability of certain antibiotics to control initial infection, relapse occurs in treated patients. The inability of antibiotics to clear this bacterial infection is in part due to persistence, an evasion mechanism against antibiotics and the effect of host defenses. Evaluation of antibiotic efficacy against B. pseudomallei revealed that up to 48% of in vitro grown populations can survive in a persister state. Toxin–antitoxin (TA) systems have been previously implicated in modulating bacterial persistence. We generated three isogenic TA mutants and found that loss of each toxin gene did not alter antibiotic persistence or macrophage survival. In response to macrophage‐induced persistence, all three toxin mutants demonstrated increased intracellular susceptibility to levofloxacin which in part was due to the inability of the mutants to induce persistence after nitric oxide or nutrient starvation. In an inhalational model of murine melioidosis, both ΔBPSS0395 and ΔBPSS1584 strains were attenuated, and treatment with levofloxacin led to significant reduction in lung colonisation and reduced splenic colonisation by ΔBPSS0395. Based on our findings, these toxins deserve additional evaluation as putative therapeutic targets.

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“…This system induces postsegregational killing of cells that have not received such plasmid after cell division, therefore ensuring plasmid transmission to the descent. Moreover, a second module encoding a YdcE-YdcD TA system (Pellegrini et al 2005) is present in this region of the CoDiRO plasmid, whose role is to induce cells to enter in a dormant persistent state of low metabolic activity when subjected to diverse stresses (Merfa et al 2016;Muranaka et al 2012;Muthuramalingam et al 2016). An addiction module annotated by RAST as a transcriptional regulator of the ArsR family is present between the two components of the YdcE-YdcD TA system.…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Analysis Provides Evidence on the Genetic Relatedness of the EmergentXylella fastidiosaGenotype in Italy to Isolates from Central America

et al. 2017

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Xylella fastidiosa is a plant-pathogenic bacterium recently introduced in Europe that is causing decline in olive trees in the South of Italy. Genetic studies have consistently shown that the bacterial genotype recovered from infected olive trees belongs to the sequence type ST53 within subspecies pauca. This genotype, ST53, has also been reported to occur in Costa Rica. The ancestry of ST53 was recently clarified, showing it contains alleles that are monophyletic with those of subsp. pauca in South America. To more robustly determine the phylogenetic placement of ST53 within X. fastidiosa, we performed a comparative analysis based on single nucleotide polymorphisms (SNPs) and the study of the pan-genome of the 27 currently public available whole genome sequences of X. fastidiosa. The resulting maximum-parsimony and maximum likelihood trees constructed using the SNPs and the pan-genome analysis are consistent with previously described X. fastidiosa taxonomy, distinguishing the subsp. fastidiosa, multiplex, pauca, sandyi, and morus. Within the subsp. pauca, the Italian and three Costa Rican isolates, all belonging to ST53, formed a compact phylotype in a clade divergent from the South American pauca isolates, also distinct from the recently described coffee isolate CFBP8072 imported into Europe from Ecuador. These findings were also supported by the gene characterization of a conjugative plasmid shared by all the four ST53 isolates. Furthermore, isolates of the ST53 clade possess an exclusive locus encoding a putative ATP-binding protein belonging to the family of histidine kinase-like ATPase gene, which is not present in isolates from the subspecies multiplex, sandyi, and pauca, but was detected in ST21 isolates of the subspecies fastidiosa from Costa Rica. The clustering and distinctiveness of the ST53 isolates supports the hypothesis of their common origin, and the limited genetic diversity among these isolates suggests this is an emerging clade within subsp. pauca.

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Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways

Cited by 89 publications

References 163 publications

Stress induces the transcription of toxin-antitoxin systems but does not activate toxin

Stress induces the transcription of toxin-antitoxin systems but does not activate toxin

Evaluating the role of Burkholderia pseudomallei K96243 toxins BPSS0390, BPSS0395, and BPSS1584 in persistent infection

Genome-Wide Analysis Provides Evidence on the Genetic Relatedness of the EmergentXylella fastidiosaGenotype in Italy to Isolates from Central America

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