Modeling sRNA-regulated Plasmid Maintenance

TL;DR

This paper presents a theoretical model analyzing the nonlinear dynamics of toxin-antitoxin systems for plasmid maintenance in bacteria, revealing key design features and potential therapeutic strategies involving sRNA regulation.

Contribution

It provides a systematic analysis of the parameter dependence of toxin-antitoxin regulation, identifying new design principles for efficient plasmid maintenance and therapeutic intervention.

Findings

Optimal toxin-antitoxin function requires specific mRNA and sRNA stability ratios.

Transient protein increase is crucial for plasmid maintenance.

Introducing competitor mRNA can induce toxin expression for therapy.

Abstract

We study a theoretical model for the toxin-antitoxin (hok/sok) mechanism for plasmid maintenance in bacteria. Toxin-antitoxin systems enforce the maintenance of a plasmid through post-segregational killing of cells that have lost the plasmid. Key to their function is the tight regulation of expression of a protein toxin by an sRNA antitoxin. Here, we focus on the nonlinear nature of the regulatory circuit dynamics of the toxin-antitoxin mechanism. The mechanism relies on a transient increase in protein concentration rather than on the steady state of the genetic circuit. Through a systematic analysis of the parameter dependence of this transient increase, we confirm some known design features of this system and identify new ones: for an efficient toxin-antitoxin mechanism, the synthesis rate of the toxin's mRNA template should be lower that of the sRNA antitoxin, the mRNA template should be more stable than the sRNA antitoxin, and the mRNA-sRNA complex should be more stable than the sRNA antitoxin. Moreover, a short half-life of the protein toxin is also beneficial to the function of the toxin-antitoxin system. In addition, we study a therapeutic scenario in which a competitor mRNA is introduced to sequester the sRNA antitoxin, causing the toxic protein to be expressed.