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Review
. 2020 Mar 11;202(7):e00763-19.
doi: 10.1128/JB.00763-19. Print 2020 Mar 11.

Type II Toxin-Antitoxin Systems: Evolution and Revolutions

Affiliations
Review

Type II Toxin-Antitoxin Systems: Evolution and Revolutions

Nathan Fraikin et al. J Bacteriol. .

Abstract

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.

Keywords: persistence; proteolysis; stress responses; toxin-antitoxin; transcriptional regulation.

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Figures

FIG 1
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.
FIG 2
FIG 2
Roles of TA systems regarding mobile genetic elements. TA genes, as well as proteins, are represented in red (toxins) and green (antitoxins). (A) Protection against phages. Some TA systems have been shown to contribute to viral defense through a process known as “abortive infection.” Viral infection would lead to a molar excess of toxin over its cognate antitoxin by yet-unknown mechanisms, leading to the killing of infected cells, preventing phage replication and propagation. (B) Antiaddiction. Chromosomal homologs of plasmid-encoded TA systems can cross-neutralize their toxic activities. Therefore, failure to inherit a TA-encoding plasmid will not lead to postsegregational killing if a homologous TA system is encoded on the chromosome. (C) Plasmid displacement. Cells that acquire more than one plasmid from the same incompatibility group through conjugation will partition these plasmids in different daughter cells. If one of such plasmids encodes a TA system, cells that fail to inherit this plasmid will still contain TA proteins in its cytoplasm and will be killed by postsegregational killing.
FIG 3
FIG 3
Transcriptional regulation of type II TA systems. TA genes, as well as proteins, are represented in red (toxins) and green (antitoxins). (A) Transcription of canonically organized TA systems. The whole operon (antitoxin-toxin) is transcribed by a single autoregulated promoter. A lower translational efficiency of toxins ensures a molar excess of antitoxin. (B) Transcription of reverse-organized TA systems. The whole operon is generally transcribed by a single autoregulated promoter (black arrow). A molar excess of antitoxin is ensured through its exclusive transcription by other promoters (blue arrow). (C) Conditional cooperativity. Unsaturated toxin-antitoxin complexes tightly bind their operators (white boxes) to repress transcription. A molar excess of toxin leads to the formation of saturated complexes that do not bind their operators, leading to derepression of the promoter, transcription of the operon, and de novo antitoxin synthesis. (D) Repression of reverse-organized systems. Excess antitoxin binds operators (white boxes) to repress transcription of the whole operon while the antitoxin gene is still transcribed. A molar excess of toxin displaces the antitoxin from its operators, leading to derepression of the autoregulated promoter (black arrow) and transcription of the whole operon.

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