Mechanisms for Differential Protein Production in Toxin–Antitoxin Systems

Deter, Heather S.; Jensen, Roderick V.; Mather, William; Butzin, Nicholas C.

doi:10.3390/toxins9070211

Cited by 34 publications

(42 citation statements)

References 54 publications

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“…Posttranscriptional regulation of TA systems. Ribosome profiling analysis performed with E. coli K-12 grown in synthetic medium suggests that all TA systems are expressed (89,105). However, the translation efficiency of toxins appears to be lower relative to antitoxins.…”

Section: Activation Of Ta Systems: From Regulation To Phenotypesmentioning

confidence: 99%

Type II Toxin-Antitoxin Systems: Evolution and Revolutions

2020

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Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of the former. While TA systems were initially discovered on plasmids, functioning as addiction modules through a phenomenon called postsegregational killing, they were later shown to be massively present in bacterial chromosomes, often in association with mobile genetic elements. Extensive research has been conducted in recent decades to better understand the physiological roles of these chromosomally encoded modules and to characterize the conditions leading to their activation. The diversity of their proposed roles, ranging from genomic stabilization and abortive phage infection to stress modulation and antibiotic persistence, in conjunction with the poor understanding of TA system regulation, resulted in the generation of simplistic models, often refuted by contradictory results. This review provides an epistemological and critical retrospective on TA modules and highlights fundamental questions concerning their roles and regulations that still remain unanswered. FIG 1 Type II TA systems, postsegregational killing and distribution. (A) Nonviable segregant or postsegregational killing model. TA genes, as well as proteins, are represented in red (toxins) and green (antitoxins).Rectangles denote TA genes encoded on a plasmid, and round shapes denote TA proteins produced from these genes. A TA-encoding plasmid can be lost during division in a way that one of the daughter cells does not inherit a plasmid copy. In these cells, TA proteins cannot be replenished due to the absence of TA genes. Since the antitoxin is degraded while its cognate toxin is stable, the free toxin concentration will increase, exert its activity, and, in time, induce cell death, therefore killing plasmid-free segregants. (B) Distribution of type II TA systems in various E. coli reference strains generated by TAfinder (23). Asterisks indicate systems that were not validated experimentally. Parentheses include name of the prophage a TA is encoded on when applicable. The strains are MG1655 (NCBI U00096.3), a common lab strain from phylogroup A; W (CP002967.1), a soil isolate from phylogroup B1; EDL933 (AE005174.2), an enterohemorrhagic pathogen from phylogroup E; and UTI89 (CP000243.1), a uropathogen from phylogroup B2. No TA systems are conserved within these four distantly related E. coli strains.

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Section: Activation Of Ta Systems: From Regulation To Phenotypesmentioning

confidence: 99%

Type II Toxin-Antitoxin Systems: Evolution and Revolutions

2020

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“…Given the abundance and diversity of these TA systems in many bacterial species, including the pathogen Mycobacterium tuberculosis, it is reasonable to think that the cell must have evolved multiple mechanisms to ensure their stringent spatial and temporal regulation. Analysis of whole genome RNA-seq and ribosome profiling data available for the E.coli genome indeed indicate that while the mRNA levels for most type II TA systems were similar for the toxin and the antitoxin, the antitoxin protein levels can be upto two fold higher than the toxin under normal growth conditions (16). We find that these relative protein levels can be perturbed through changes in mRNA structure due to synonymous mutations.…”

Section: Discussionmentioning

confidence: 69%

“…While levels can be in principle regulated at both the transcriptional as well as the translational level, RNA-seq data from E.coli indicate that mRNA levels for the toxin and the antitoxin are not significantly different, as is expected for genes encoded by a single polycistronic mRNA (16). Ribo-seq data available for TA systems indicate that the protein synthesis rates (calculated from the ribosome densities) for the antitoxin are at least 2 fold higher than the toxin, for six TA pairs for which sufficient data is available (16). These observations together indicate that there are indeed nucleotide sequence dependent features, which allow regulation at the level of translation, leading to differential synthesis rates for the two genes in the operon.…”

Section: Introductionmentioning

confidence: 91%

“…Although the distance between the stop codon of the first gene and start codon of the second gene can vary, bioinformatics studies have shown that in the case of TA systems it is between 0-5 nucleotides (15). In some cases, the two ORFs even overlap with each other (16). Posttranslationally, the two proteins are subjected to differential degradation.…”

Section: Introductionmentioning

confidence: 99%

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Loss of function from widely distributed, synonymous mutations at single codons

Gupta

Prabha

Chandra

et al. 2019

Preprint

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Mutational tolerance inferred from laboratory-based mutational studies is typically much higher than observed natural sequence variation. Using saturation mutagenesis, we show that the ccdA antitoxin component of the ccdAB toxin-antitoxin system is unusually sensitive to mutation with over 60% of mutations leading to loss of function. Multi-base synonymous mutations at a codon display enhanced propensity to show altered phenotypes, relative to single-base ones. Such mutations modulate RNA structure, leading to altered relative translation efficiencies of the two genes in the operon, and a CcdA:CcdB protein ratio below one. These insights were used to predict and experimentally validate synonymous mutations that lead to loss of function in the unrelated relBE operon as well as the lacZ gene. Thus, synonymous mutations can have significant phenotypic effects, in the absence of overexpression or extraneous reporters. More generally, proteins are likely more sensitive to mutation than inferred from previous saturation mutagenesis studies.

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“…Also, despite multiple studies show that TA toxins can affect the stress tolerance 18-22 , these studies mostly involve artificial overexpression of the toxin which will likely never occur from the single-copy chromosomal TA locus. It is also important to note that even though several studies report that chromosomal TA loci are upregulated by stress conditions 17,23,24 , it does not necessarily mean that toxin is liberated from the antitoxin-mediated control, particularly, when considering that antitoxin is produced at a much higher rate than the toxin 25,26 .…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas putidachromosomal toxin-antitoxin systems carry neither clear fitness benefits nor big costs

Rosendahl

Tamman

Brauer

et al. 2020

Preprint

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14Chromosomal toxin-antitoxin (TA) systems are widespread genetic elements among bacteria, yet, 15 despite extensive studies in the last decade, their biological importance remains ambivalent. The ability 16 of TA-encoded toxins to affect stress tolerance supports the hypothesis of TA systems being associated 17 with stress adaptation. However, the deletion of TA genes has usually no fitness consequences, 18 supporting the selfish elements hypothesis. Here, we aimed to evaluate the cost and benefits of 19 chromosomal TA systems to Pseudomonas putida. We show that multiple TA systems do not confer 20 fitness benefits to this bacterium as deletion of 13 TA loci does not influence stress tolerance, 21 persistence and biofilm formation. Our results instead show that TA loci are costly and decrease the 22 competitive fitness of P. putida. Still, the cost of multiple TA systems is low and detectable in certain 23 conditions only. Construction of antitoxin deletion strains showed that only five TA systems code for 24 toxic proteins, while other TA loci have evolved towards reduced toxicity and encode non-toxic or 25 moderately potent proteins. Analysis of P. putida TA systems' homologs among fully sequenced 26 Pseudomonads suggests that the TA loci have been subjected to purifying selection and that TA systems 27 spread among bacteria by horizontal gene transfer.28

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Mechanisms for Differential Protein Production in Toxin–Antitoxin Systems

Cited by 34 publications

References 54 publications

Type II Toxin-Antitoxin Systems: Evolution and Revolutions

Type II Toxin-Antitoxin Systems: Evolution and Revolutions

Loss of function from widely distributed, synonymous mutations at single codons

Pseudomonas putidachromosomal toxin-antitoxin systems carry neither clear fitness benefits nor big costs

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