Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy.
Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy.
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DOI：
10.1371/journal.pcbi.1003174
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发表时间：
2013
影响因子：
4.3
通讯作者：
Mitarai N
中科院分区：
文献类型：
--
作者：
Cataudella I;Sneppen K;Gerdes K;Mitarai N
许多毒素-抗毒素操纵子受毒素/抗毒素比例的调节，其机制统称为“条件协同”。毒素和抗毒素以不同的化学计量比形成异构体，中间比例的复合物作为转录抑制因子效果最好。这允许在低毒素水平下进行转录，在中等毒素水平下进行强烈抑制，然后在高毒素水平下进行转录。这种监管有两个有趣的特点；首先，它对其中一种蛋白质的浓度提供了非单调的响应，其次，它为功能异构体的隔离介导的超灵敏度打开了大门。我们探索了简单反馈基序中条件调节的可能函数，并表明它可以在广泛的参数范围内提供双稳定性。然后，我们证明了毒素-抗毒素系统中的条件协同性与自由毒素的生长抑制活性相结合，可以介导生长状态和休眠状态之间的双稳定性。抗生素对许多致病菌的有效性受到多药耐受性的影响。这是由于一小部分细菌在使用抗生素时恰好处于休眠、不分裂状态，因此不会被杀死。这些细菌被称为持久性细菌。揭开这一现象背后的基本机制是克服持续和反复感染的必要的第一步。实验表明，在大肠杆菌细胞内，持久性的形成与毒素和抗毒素之间的斗争有关。毒素抑制细胞生长，但通过形成复合物被抗毒素中和。这些蛋白质也通过这种复合体来调节它们自己的生产，从而形成一个控制细菌生长的反馈系统。在这项工作中，我们提供了反馈模块的数学建模和探索其能力。我们发现，与游离毒素相关的生长减少的自我调节允许细胞在两种状态之间保持双稳态：一种是抗毒素主导的正常生长状态，或者是由毒素活性引起的休眠状态。后者可以是持久状态的最简单描述。毒素-抗毒素系统是混合反馈设计的一个强有力的例子，它可以支持表观遗传学。
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. The effectiveness of antibiotics on many pathogenic bacteria is compromised by multidrug tolerance. This is caused by a small sub-population of bacteria that happen to be in a dormant, non-dividing state when antibiotics are applied and thus are protected from being killed. These bacteria are called persisters. Unraveling the basic mechanism underlying this phenomenon is a necessary first step to overcome persistent and recurring infections. Experiments have shown a connection between persister formation and the battle between a toxin and its antitoxin inside an E. coli cell. Toxin inhibits the cell growth but is neutralized by the antitoxin by forming a complex. The proteins also regulate their own production through this complex, thereby forming a feedback system that controls the growth of the bacterium. In this work we provide mathematical modeling of the feedback module and explore its abilities. We find that the auto-regulation with reduced growth associated with free toxins allows the cell to be bistable between two states: an antitoxin-dominated, normal growing one, or a dormant one caused by the activity of the toxin. The latter can be the simplest description of persister state. The toxin-antitoxin system presents a powerful example of mixed feedback design, which can support epigenetics.
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影响因子：
5.6
作者：
Overgaard M;Borch J;Gerdes K
通讯作者：
Gerdes K
影响因子：
9.9
作者：
Chen D;Arkin AP
通讯作者：
Arkin AP
DOI：
10.1016/j.str.2012.08.017
发表时间：
2012-10-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Bøggild A;Sofos N;Andersen KR;Feddersen A;Easter AD;Passmore LA;Brodersen DE
通讯作者：
Brodersen DE
DOI：
10.1073/pnas.251327898
发表时间：
2001-12-04
影响因子：
11.1
作者：
Christensen, SK;Mikkelsen, M;Gerdes, K
通讯作者：
Gerdes, K
影响因子：
14.9
作者：
Pandey DP;Gerdes K
通讯作者：
Gerdes K