Toxin–antitoxin systems: why so many, what for?
Introduction
Toxin–antitoxin (TA) systems are small genetic modules consisting in general of 2 components, a stable toxin and its labile antitoxin. TA systems are of 3 types, depending on the antitoxin nature and mode of action. While toxins are always proteins, antitoxins are either RNAs (type I and III) or proteins (type II) (see Box 1). Type I and II systems were discovered on plasmids in the 80s [1, 2], while type III was discovered in 2009 and is represented so far by a unique example [3••]. Plasmid-encoded TA systems participate in plasmid stabilization by a mechanism denoted as post-segregational killing [4] or addiction [5]. The molecular mechanism underlying this phenomenon relies on differential stability of the 2 components. When a plasmid copy is not transmitted to daughter bacteria, the antitoxin and toxin pool is not replenished. Since the antitoxin is labile and rapidly degraded, the toxin is released from inhibition, leading to the killing of plasmid-free cells. As a consequence at the population level, the plasmid prevalence is increased (number of plasmid containing cells/total number of cells).
Homologues of TA systems were subsequently found in chromosomes of eu- and archaea bacteria. Type II systems appear to be widespread in chromosomes and often found in multiple copies within genomes (see Table 1 for the currently known type II toxins and their characteristics) [6•, 7, 8, 9]. Type I systems appear to be less represented [10••]. The surprising abundance of these genetic entities, at least type II systems, in bacterial genomes raises interesting questions regarding their possible biological roles, their evolution and their mobility.
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Coping with stress
Current hypotheses propose that TA systems are involved in stress management either by promoting altruistic sacrifice of a large fraction of the population (programmed cell death hypothesis, PCD) or by inducing a dormant stage that allows cells to cope with stress (stasis). These hypotheses have emerged mainly from the study of 2 E. coli K-12 type II systems (mazEF and relBE) in which toxins are mRNAs interferases and inhibit translation. The general principle for TA systems activation relies
Diversity, abundance, origin and evolution
Type II TA systems are thought to be part of the mobilome and to move from one genome to another through horizontal gene transfer [38, 39]. This certainly accounts for the surprisingly high number of type II TA systems present in most eu- and archaea-bacterial chromosomes [6•, 7, 8, 9]. In addition to the 10 current families of toxins (see Table 1), predictions revealed the existence of a dozen novel toxin and antitoxin families ([6•], Geeraerts, Leplae, Hallez and Van Melderen, in preparation).
Concluding remarks
Although type II TA systems might in specific cases be hijacked by host regulatory networks such as the solitary MazF toxin from M. xanthus [46], it is tempting to speculate that they might operate at the selfish level to promote their own ‘survival’ at the expense of the host as proposed by Kobayashi for restriction-modification systems [47]. When located on mobile genetic elements, these systems appear to promote their stability as well as exclusion of competitors DNA which might be a
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
I thank Didier Mazel, Damien Geeraerts and Nathalie Goeders for reviewing the manuscript as well as Manuel Saavedra De Bast, Johan Timmermans, Damien Geeraerts and Julien Guglielmini for exciting debates on the selfish gene theory. I am grateful to FNRS (FRSM-3.4530.04) for support of research in my laboratory.
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