In spite of the ubiquity of chromosomally encoded TA systems in bacteria and archaea, their functions remained enigmatic for many years. They do not act on other cells in the population, and hence-in contrast to toxic proteins such as colicins-they are not used in battles between bacteria. Citation 19, Citation 20 It is important to note that all TA system toxins work from within and affect only the cells that produce them. However, an alternative view suggests toxin-dependent altruistic suicide (programmed cell death) under certain conditions-such as exposure to some antibiotics-and is, at this point, controversial. Citation 10, Citation 11, Citation 15 - Citation 18 Generally, stress-induced toxicity tends to decrease growth rate or arrest growth entirely. Citation 13, Citation 14 Toxins have quite a diverse array of different cellular targets and affect for instance DNA replication, translation, and membrane integrity. Citation 12 A third, recently discovered type III system is remarkable in that a pseudoknot-containing RNA (the antitoxin) directly binds to the toxin to inhibit its activity. Proteolytic destabilization of the antitoxin is performed by proteases and activates toxicity. Citation 5, Citation 8, Citation 11 The complex formed by both proteins regulates the operon that encodes the TA protein pair. Typical examples are relB/relE and mazE/mazF. Citation 9, Citation 10 Type II loci encode a toxin whose activity is blocked by an antitoxin protein. The antitoxin RNA prevents translation/ promotes degradation of the toxin mRNA by an antisense mechanism. Type I TA systems-as for instance the prototypical hok/sok module mentioned above-consist of a toxic protein and a small RNA (sRNA) that acts as the antitoxin. Irrespective of their presence on chromosomes or plasmids, TA systems are today broadly classified by the components they use. coli harbors more than 15 Citation 4, Citation 5 and Mycobacterium tuberculosis more than 80 TA loci. Citation 2, Citation 3 Several years after the discovery of hok/sok and other unrelated PSK systems, it was found that TA systems were also encoded by the chromosomes of numerous bacterial and archaeal species, sometimes in staggering numbers. The best studied such system is hok/sok of plasmid R1 which has been investigated in great detail by the Gerdes group. Thus, the toxin kills plasmid-free cells, whereas plasmid-containing cells are unaffected due to continuous de novo synthesis of the antitoxin. Hence, loss of the TA locus (i.e., plasmid loss) quickly results in decreased antitoxin levels, whereas the stable toxin protein or the stable toxin mRNA remains present in the absence of its gene, eventually entailing toxin synthesis or activity. PSK systems rely on a key property that subsequently was shown to encompass all other such systems: the toxin is stable, and the antitoxin unstable. Toxin-antitoxin (TA) systems were initially discovered in bacterial plasmids Citation 1, Citation 2 where they confer stability of maintenance through post-segregational killing (PSK).
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