Regulation of ubiquitous bacterial type II toxin-antitoxin (TA) gene pairs occurs via a negative feedback loop whereby their expression is typically responsive to changing levels of toxins at the transcriptional level similar to a molecular rheostat. While this mechanism can explain how certain TA complexes are regulated, accumulating evidence suggests diversity in this regulation. One system for which the negative feedback loop is not well defined is the plasmid-encoded HigBHigA TA pair originally identified in a post-operative infection with antibiotic resistant Proteus vulgaris. In contrast to other type II TA modules, each hig operator functions independently and excess toxin does not contribute to increased transcription in vivo. Structures of two different oligomeric complexes of HigBHigA bound to its operator DNA reveal similar interactions are maintained suggesting plasticity in how hig is repressed. Consistent with this result, molecular dynamic simulations reveal both oligomeric states exhibit similar dynamics. Further, engineering a dedicated trimeric HigBHigA complex does not regulate transcriptional repression. We propose that HigBHigA functions via a simple on/off transcriptional switch regulated by antitoxin proteolysis rather than a molecular rheostat. The present studies thus expand the known diversity of how these abundant bacterial protein pairs are regulated.

中文翻译：

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寻常变形杆菌中抗性质粒Rts1的hig毒素-抗毒素基因座转录调控的分子机制

普遍存在的细菌II型毒素-抗毒素（TA）基因对的调节是通过负反馈回路进行的，因此它们的表达通常在类似于分子变阻器的转录水平上响应于毒素水平的变化。尽管这种机制可以解释某些TA复合物是如何被调控的，但越来越多的证据表明这种调控的多样性。负反馈环未明确定义的一种系统是质粒编码的HigBHigA TA对，最初是在对抗生素耐药的寻常型变形杆菌感染后感染中鉴定的。与其他II型TA模块相反，每个hig操作者独立地起作用，并且过量的毒素不会促进体内转录的增加。HigBHigA的两个不同寡聚复合物的结构与其操作员DNA结合，揭示了相似的相互作用得以维持，这表明在抑制hig方面具有可塑性。与此结果一致，分子动力学模拟表明两种低聚物状态都表现出相似的动力学。此外，工程化专用的三聚体HigBHigA复合体不能调节转录阻遏。我们建议HigBHigA通过一个简单的开/关转录开关来起作用，该开关由抗毒素蛋白水解而不是分子变阻器调节。因此，本研究扩展了如何调节这些丰富的细菌蛋白对的已知多样性。