Transcriptional and translational regulation in Arc protein network of Escherichia coli's stress response

TL;DR

This paper investigates the complex regulation of sigma^s in E. coli under oxidative stress, highlighting the interplay of transcriptional and sRNA-mediated translational control involving ArcA, ArcB, and ArcZ, with insights from kinetic modeling and stochastic simulations.

Contribution

It provides a detailed kinetic model of ArcA, ArcB, and ArcZ interactions, revealing how sRNA-mediated regulation influences stress response dynamics in E. coli.

Findings

Destabilisation of ArcB mRNA by ArcZ is crucial for desired regulatory states.

Increased ArcZ-ArcB affinity leads to more transcriptional bursts.

High phosphorylation rates affect the transition thresholds in the regulatory network.

Abstract

Recently, there has been a lot of effort in understanding sRNA mediated regulation of gene expression and how this mode of regulation differs from transcriptional regulation.In E.coli, in the presence of oxidative stress, the synthesis of sigma^s is regulated through an interesting mechanism involving both transcriptional and sRNA-mediated translational regulation. The key regulatory factors involved in transcriptional and translational regulation are ArcA and ArcB proteins and ArcZ sRNA, respectively. Phosphorylated ArcA, in a feedforward mechanism, represses the transcriptions sigma^s and ArcZ sRNA with the latter being a post-transcriptional activator for sigma^s. Through a feedback mechanisms, ArcZ sRNA destabilises ArcB mRNA and regulates the level of ArcB protein, a kinase that phosphorylates ArcA. The oxygen and energy availability is expected to influence the ArcA phosphorylation rate and, as a consequence, in equilibrium, the system is likely to be in either a high ArcB (low ArcZ) or a low ArcB (high ArcZ) state. Kinetic modelling studies suggest that the rate of destabilisation of ArcB mRNA by ArcZ sRNA must be appropriately tuned for achieving the desired state. In particular, for a high phosphorylation rate, the transition from a low to a high ArcZ synthesis regime with the increase in sRNA-mRNA interaction is similar to the threshold-linear response observed earlier. Further, we show that the mRNA destabilisation by sRNA might be, in particular, beneficial in the low phosphorylation state for having the right concentration levels of ArcZ and ArcB. Stochastic simulation results suggest that as the ArcZ-ArcB binding affinity is increased, the probability distribution for the number of ArcZ molecules becomes flatter indicating frequently occurring transcriptional bursts of varying strengths.