Chaperone-mediated stress-sensing in Mycobacterium tuberculosis enables fast activation and sustained response

Abstract

Dynamical properties of gene-regulatory networks are tuned to ensure bacterial survival. In mycobacteria, MprAB-σ E network responds to the presence of stressors, such as surfactants causing surface stress. Positive feedback loops in this network were previously predicted to cause hysteresis, i.e. different responses to identical stressor levels for pre-stressed and unstressed cells. Here we show that hysteresis does not occur in non-pathogenic Mycobacterium smegmatis but occurs in Mycobacterium tuberculosis (Mtb). However, the observed rapid temporal response in Mtb is inconsistent with the model predictions. To reconsolidate these observations, we propose a new mechanism for stress-sensing: release of MprB from the inhibitory complex with chaperone DnaK upon the stress exposure. Using modeling and parameter fitting, we demonstrate that this mechanism can accurately describe the experimental observations. Furthermore, we predict perturbations in DnaK expression that can strongly affect dynamical properties. Experiments with these perturbations agree with model predictions, confirming our proposed stress-sensing mechanism.