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

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  • Authors: Ana María Hernández-Arriaga1, Wai Ting Chan2, Manuel Espinosa3, Ramón Díaz-Orejas4
  • Editors: Marcelo E. Tolmasky5, Juan Carlos Alonso6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; 2: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; 3: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; 4: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; 5: California State University, Fullerton, CA; 6: Centro Nacional de Biotecnología, Cantoblanco, Madrid, Spain
    • Source: microbiolspec October 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.PLAS-0009-2013
  • Received 22 November 2013 Accepted 27 November 2013 Published 24 October 2014
  • Ramón Díaz-Orejas, •••
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  • Abstract:

    Toxin-antitoxin (TA) systems are small genetic modules formed by a stable toxin and an unstable antitoxin that are widely present in plasmids and in chromosomes of Bacteria and Archaea. Toxins can interfere with cell growth or viability, targeting a variety of key processes. Antitoxin inhibits expression of the toxin, interacts with it, and neutralizes its effect. In a plasmid context, toxins are kept silent by the continuous synthesis of the unstable antitoxins; in plasmid-free cells (segregants), toxins can be activated owing to the faster decay of the antitoxin, and this results in the elimination of these cells from the population (ostegregational illing [PSK]) and in an increase of plasmid-containing cells in a growing culture. Chromosomal TA systems can also be activated in particular circumstances, and the interference with cell growth and viability that ensues contributes in different ways to the physiology of the cell. In this article, we review the conditional activation of TAs in selected plasmidic and chromosomal TA pairs and the implications of this activation. On the whole, the analysis underscores TA interactions involved in PSK and points to the effective contribution of TA systems to the physiology of the cell.

  • Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2014. Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond. Microbiol Spectrum 2(5):PLAS-0009-2013. doi:10.1128/microbiolspec.PLAS-0009-2013.

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/content/journal/microbiolspec/10.1128/microbiolspec.PLAS-0009-2013
2014-10-24
2019-10-17

Abstract:

Toxin-antitoxin (TA) systems are small genetic modules formed by a stable toxin and an unstable antitoxin that are widely present in plasmids and in chromosomes of Bacteria and Archaea. Toxins can interfere with cell growth or viability, targeting a variety of key processes. Antitoxin inhibits expression of the toxin, interacts with it, and neutralizes its effect. In a plasmid context, toxins are kept silent by the continuous synthesis of the unstable antitoxins; in plasmid-free cells (segregants), toxins can be activated owing to the faster decay of the antitoxin, and this results in the elimination of these cells from the population (ostegregational illing [PSK]) and in an increase of plasmid-containing cells in a growing culture. Chromosomal TA systems can also be activated in particular circumstances, and the interference with cell growth and viability that ensues contributes in different ways to the physiology of the cell. In this article, we review the conditional activation of TAs in selected plasmidic and chromosomal TA pairs and the implications of this activation. On the whole, the analysis underscores TA interactions involved in PSK and points to the effective contribution of TA systems to the physiology of the cell.

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Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond
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Citation: Hernández-Arriaga A, Chan W, Espinosa M, Díaz-Orejas R. 2014. Conditional activation of toxin-antitoxin systems: postsegregational killing and beyond. microbiolspec 2(5): doi:10.1128/microbiolspec.PLAS-0009-2013
/content/microbiolspec/10.1128/microbiolspec.PLAS-0009-2013.fig1
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).
microbiolspec/2/5/PLAS-0009-2013-fig1_thmb.gif
microbiolspec/2/5/PLAS-0009-2013-fig1.gif
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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).

Source: microbiolspec October 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.PLAS-0009-2013
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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.
microbiolspec/2/5/PLAS-0009-2013-fig2_thmb.gif
microbiolspec/2/5/PLAS-0009-2013-fig2.gif
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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.

Source: microbiolspec October 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.PLAS-0009-2013
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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).
microbiolspec/2/5/PLAS-0009-2013-fig3_thmb.gif
microbiolspec/2/5/PLAS-0009-2013-fig3.gif
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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).

Source: microbiolspec October 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.PLAS-0009-2013
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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.
microbiolspec/2/5/PLAS-0009-2013-fig4_thmb.gif
microbiolspec/2/5/PLAS-0009-2013-fig4.gif
Image of FIGURE 4

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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.

Source: microbiolspec October 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.PLAS-0009-2013
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