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Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy.

Cataudella I, Sneppen K, Gerdes K, Mitarai N - PLoS Comput. Biol. (2013)

Bottom Line: Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor.Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers.We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

View Article: PubMed Central - PubMed

Affiliation: Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT
Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined "conditional cooperativity". Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription at low toxin level, strong repression at intermediate toxin level, and then again transcription at high toxin level. Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers. We explore possible functions of conditional regulation in simple feedback motifs, and show that it can provide bistability for a wide range of parameters. We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

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Schematic summary of the role of conditional regulation in persister formation.The red curves show the toxin production rate and the blue lines give the degradation rate, both from eq. (6). Both terms depend on , and here we make approximation that  is always in steady state (eq. 7 with ) for given , because dynamics of  is much faster than  due to high production and degradation rate. Since production term of  and  are proportional to each other and  is degraded at a constant rate, resulting  concentration is proportional to the production term of  (red curves). The scales of curves are modified from actual functional forms so that the characteristic behaviours can be grasped easily. The ultra-sensitivity mediated by protein-protein binding combined with feedback from free toxin activity is reflected in the peak of the production rate and drop of the degradation rate, resulting in bistability of the system. This accounts for the type II persister where a cell can spontaneously switch to and out of the persister state. The non-monotonicity of the conditional regulation secures that some toxins are stored in antitoxin dominated state, helping the transition to the stress-induced activation of toxin [6], which becomes the base for type I persister formation.
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pcbi-1003174-g005: Schematic summary of the role of conditional regulation in persister formation.The red curves show the toxin production rate and the blue lines give the degradation rate, both from eq. (6). Both terms depend on , and here we make approximation that is always in steady state (eq. 7 with ) for given , because dynamics of is much faster than due to high production and degradation rate. Since production term of and are proportional to each other and is degraded at a constant rate, resulting concentration is proportional to the production term of (red curves). The scales of curves are modified from actual functional forms so that the characteristic behaviours can be grasped easily. The ultra-sensitivity mediated by protein-protein binding combined with feedback from free toxin activity is reflected in the peak of the production rate and drop of the degradation rate, resulting in bistability of the system. This accounts for the type II persister where a cell can spontaneously switch to and out of the persister state. The non-monotonicity of the conditional regulation secures that some toxins are stored in antitoxin dominated state, helping the transition to the stress-induced activation of toxin [6], which becomes the base for type I persister formation.

Mentions: Conditional regulation is an example of mixed feedback motifs [30], where protein-protein interactions and transcriptional repression are combined. In natural systems, protein-protein interaction mediated bistable switch was previously found for example in the epigenetic switch of the TP901 phage [23], [25] and in the sigma-factor/antisigma-factor system [24]. Conditional cooperativity in TA systems opens for a toolbox of regulatory units that can exhibit sufficient bistability to support also epigenetics. When removing the toxic ability of toxin, which has been done for RelE [3], and separating antitoxin from the operon to allow independent control, the strong binding between RelE and RelB should provide extreme ultrasensitivity, and thus very well separated metastable states. This conditional cooprativity-mediated bistability is the base for the bistability in full TA systems, and thus for the type II persister formation [12], [13], where a cell can spontaneously switch between the dormant state and the growing state (Fig. 5).


Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy.

Cataudella I, Sneppen K, Gerdes K, Mitarai N - PLoS Comput. Biol. (2013)

Schematic summary of the role of conditional regulation in persister formation.The red curves show the toxin production rate and the blue lines give the degradation rate, both from eq. (6). Both terms depend on , and here we make approximation that  is always in steady state (eq. 7 with ) for given , because dynamics of  is much faster than  due to high production and degradation rate. Since production term of  and  are proportional to each other and  is degraded at a constant rate, resulting  concentration is proportional to the production term of  (red curves). The scales of curves are modified from actual functional forms so that the characteristic behaviours can be grasped easily. The ultra-sensitivity mediated by protein-protein binding combined with feedback from free toxin activity is reflected in the peak of the production rate and drop of the degradation rate, resulting in bistability of the system. This accounts for the type II persister where a cell can spontaneously switch to and out of the persister state. The non-monotonicity of the conditional regulation secures that some toxins are stored in antitoxin dominated state, helping the transition to the stress-induced activation of toxin [6], which becomes the base for type I persister formation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757081&req=5

pcbi-1003174-g005: Schematic summary of the role of conditional regulation in persister formation.The red curves show the toxin production rate and the blue lines give the degradation rate, both from eq. (6). Both terms depend on , and here we make approximation that is always in steady state (eq. 7 with ) for given , because dynamics of is much faster than due to high production and degradation rate. Since production term of and are proportional to each other and is degraded at a constant rate, resulting concentration is proportional to the production term of (red curves). The scales of curves are modified from actual functional forms so that the characteristic behaviours can be grasped easily. The ultra-sensitivity mediated by protein-protein binding combined with feedback from free toxin activity is reflected in the peak of the production rate and drop of the degradation rate, resulting in bistability of the system. This accounts for the type II persister where a cell can spontaneously switch to and out of the persister state. The non-monotonicity of the conditional regulation secures that some toxins are stored in antitoxin dominated state, helping the transition to the stress-induced activation of toxin [6], which becomes the base for type I persister formation.
Mentions: Conditional regulation is an example of mixed feedback motifs [30], where protein-protein interactions and transcriptional repression are combined. In natural systems, protein-protein interaction mediated bistable switch was previously found for example in the epigenetic switch of the TP901 phage [23], [25] and in the sigma-factor/antisigma-factor system [24]. Conditional cooperativity in TA systems opens for a toolbox of regulatory units that can exhibit sufficient bistability to support also epigenetics. When removing the toxic ability of toxin, which has been done for RelE [3], and separating antitoxin from the operon to allow independent control, the strong binding between RelE and RelB should provide extreme ultrasensitivity, and thus very well separated metastable states. This conditional cooprativity-mediated bistability is the base for the bistability in full TA systems, and thus for the type II persister formation [12], [13], where a cell can spontaneously switch between the dormant state and the growing state (Fig. 5).

Bottom Line: Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor.Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers.We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

View Article: PubMed Central - PubMed

Affiliation: Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT
Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined "conditional cooperativity". Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription at low toxin level, strong repression at intermediate toxin level, and then again transcription at high toxin level. Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers. We explore possible functions of conditional regulation in simple feedback motifs, and show that it can provide bistability for a wide range of parameters. We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

Show MeSH