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Chapter 10 : Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond

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Abstract:

Toxin-antitoxin (TA) genes are small genetic modules coding for a toxin and an antitoxin. Toxins inhibit cell proliferation or viability, and antitoxins neutralize this inhibition. The toxin (always a protein) is the stable component and the antitoxin (a protein or a regulatory RNA) is less stable, and this differential stability plays an important role in the conditional activation of TAs. The term ostegregational illing (PSK) was introduced to define the toxin-dependent elimination of plasmid-free cells that occurs as a consequence of the loss of TA-containing plasmids at cell division. Conditional activation of the toxins in these cells requires a differential decay of the antitoxins compared with the toxins. This differential stability is due to the action of proteases or RNases on the antitoxin half-life. In plasmid-containing cells, the toxin is kept under control because the levels of the antitoxin are replenished by synthesis. In plasmid-free cells, the toxins are activated as the consequence of the faster decay of the antitoxins, and this leads to the elimination of these cells from the population (PSK) and to an increase of the percentage of plasmid-containing cells ( ) ( Fig. 1 ). Since the discovery of TA systems as auxiliary maintenance modules in plasmids ( ), they have been found in phages and chromosomes of Bacteria and Archaea, often in multiple copies ( ). Conditional activation of TA pairs has also been detected in chromosomal systems in response to particular signals. Furthermore, some of the chromosomal TA systems have the potential to stabilize plasmids via PSK, implying that the differential stability of toxins and antitoxins plays a role in their activation. Conditional activation of TA systems has consequences beyond plasmid stabilization, such as in plasmid competition, phage-abortive infection, stress response, stabilization of particular genomic regions, biofilm formation, and bacterial persistence ( ). Most recently, TA systems have been found tightly associated with other defense systems that can be found in Archaea and in Bacteria and that include the so-called CRISPR-Cas immunity system ( ).

Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2015. Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond, p 175-192. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0009-2013

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Mobile Genetic Elements
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Figures

Image of Figure 1
Figure 1

TAs determine plasmid maintenance by PSK. A bacterial population contains cells with a plasmid that encodes a TA system. In plasmid-containing cells, both the antitoxin and the toxin will be continuously expressed. The inhibitory activity of the toxin will keep neutralized its cognate antitoxin. In plasmid-free cells, a specific depletion of the antitoxin levels by cellular RNases or proteases activates the more stable toxin. This activation induces cell death or arrests the growth of plasmid-free cells (PSK) and increases the number of plasmid-containing cells in the growing population (plasmid maintenance phenotype). doi:10.1128/microbiolspec.PLAS-0009-2013.f1

Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2015. Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond, p 175-192. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0009-2013
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Image of Figure 2
Figure 2

TA regulation and activation. TA systems are operons that codify a toxin (T) and an antitoxin (A). They share common features: (i) Expression of the operon is regulated at the transcriptional or posttranscriptional levels; (ii) the antitoxin binds and neutralizes the toxic activity of the toxin; and (iii) the antitoxin is unstable and the toxin is stable. The decay of the more unstable antitoxin leads to toxin activation. and show the basic features of the regulation and activation of type I, II, and III TAs. Type I TAs: the antitoxin is a small antisense RNA, and the toxin is a protein; processing of the toxin mRNA and cleavage of RNA-RNA hybrids regulate the activity of these systems. Type II TAs: Both toxin and antitoxin are proteins; proteases targeting specifically the antitoxin regulate activation of the toxin. Type III TAs: the antitoxin is an RNA that inactivates the toxin. Toxin activation can occur in response to bacteriophage infection leading to the elimination of these cells and thus preventing the spread of the infection. doi:10.1128/microbiolspec.PLAS-0009-2013.f2

Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2015. Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond, p 175-192. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0009-2013
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Image of Figure 3
Figure 3

PSK in plasmid maintenance and in plasmid competition. The random distribution, at cell division, of two plasmid copies with or without a TA system, are shown, in and , respectively. Filled circle, plasmid containing TA; open circle, plasmid without TA. Toxin is activated in cells that lose the TA plasmid, and this results in cell death or inhibition of cell proliferation (PSK). Elimination of plasmid-free cells (crossed cell) increases the proportion of plasmid-containing cells in the culture (maintenance phenotype). In , only one of the two plasmids contains a TA system. Proliferation of cells containing a TA-free plasmid requires the presence of the TA plasmid. This gives a reproductive advantage to cells containing the TA plasmid (competition). doi:10.1128/microbiolspec.PLAS-0009-2013.f3

Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2015. Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond, p 175-192. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0009-2013
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Image of Figure 4
Figure 4

Proposed model for a possible role of TA in stabilizing ICE by PSK during conjugative transfer. Under normal conditions, the TA genes (antitoxin gene is depicted as blue arrow; toxin gene is represented by red arrow) on the ICE (purple fragment) are expressed at a basal level within the chromosome. Toxin and antitoxin proteins (red and blue ovals, respectively) form tight complexes that are inert to the cell. During conjugative transfer, the ICE is excised from the chromosome and forms a circular mobilome. The ICE replicates (one copy or more), and one copy of the ICE is transferred to the recipient cell through rolling circle (single-stranded DNA is transferred to the recipient cell and its complimentary DNA strand will be degraded gradually in the donor cell); another copy of the ICE remains in the donor cell. In the donor cell, the ICE is integrated back into the chromosome, while the transferred single-stranded DNA in the recipient cell will replicate to form an intact ICE, followed by integration into the chromosome. The ICE is transferred to the recipient cell without replication in the donor cells. Since the donor cell has lost the TA-containing ICE, the remaining TA complexes will be triggered. The antitoxin proteins that are more susceptible to the degradation of the host proteases are degraded and not replenished owing to the loss of the TA-containing ICE, thus releasing the toxin activity that poisons the donor cell. On the other hand, the recipient cell, which has newly acquired a TA-containing ICE, will thus incorporate the ICE into the chromosome. This recipient cell is subject to the same fate as the donor cell if the ICE is lost. doi:10.1128/microbiolspec.PLAS-0009-2013.f4

Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2015. Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond, p 175-192. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0009-2013
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