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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, the MprAB-σ^E network responds to the presence of stressors, such as surfactants that cause surface stress. Positive feedback loops in this network were previously predicted to cause hysteresis, i.e., different responses to identical stressor levels for prestressed and unstressed cells. Here, we show that hysteresis does not occur in nonpathogenic Mycobacterium smegmatis but does occur in Mycobacterium tuberculosis However, the observed rapid temporal response in M. tuberculosis is inconsistent with the model predictions. To reconcile these observations, we implement a recently proposed mechanism for stress sensing, namely, the release of MprB from the inhibitory complex with the 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 the role of DnaK in fast and sustained response.IMPORTANCE Gene regulatory networks controlling stress response in mycobacterial species have been linked to persistence switches that enable bacterial dormancy within a host. However, the mechanistic basis of switching and stress sensing is not fully understood. In this paper, combining quantitative experiments and mathematical modeling, we uncover how interactions between two master regulators of stress response-the MprAB two-component system (TCS) and the alternative sigma factor σ^E-shape the dynamical properties of the surface stress network. The result show hysteresis (history dependence) in the response of the pathogenic bacterium M. tuberculosis to surface stress and lack of hysteresis in nonpathogenic M. smegmatis Furthermore, to resolve the apparent contradiction between the existence of hysteresis and fast activation of the response, we utilize a recently proposed role of chaperone DnaK in stress sensing. These result leads to a novel system-level understanding of bacterial stress response dynamics.

SUBMITTER: Rao SD

PROVIDER: S-EPMC8561658 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The bacterial pathogen Mycobacterium tuberculosis is the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterized M. tuberculosis protein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologs in most bacterial lineages and appears to function analogously to the well-characterized Escherichia coli redox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally coregulated with hsp60 and hsp70 chaperone genes in M. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded protein in vitro and promotes its refolding by the M. tuberculosis Hsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and can associate with many other M. tuberculosis proteins. We therefore propose that Rv0991c, which we named "Ruc" (redox-regulated protein with unstructured C terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress.IMPORTANCE M. tuberculosis infections are responsible for more than 1 million deaths per year. Developing effective strategies to combat this disease requires a greater understanding of M. tuberculosis biology. As in all cells, protein quality control is essential for the viability of M. tuberculosis, which likely faces proteotoxic stress within a host. Here, we identify an M. tuberculosis protein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial superkingdom. Additionally, we found that oxidized Ruc promotes the protein-folding activity of the essential M. tuberculosis Hsp70 chaperone system. This work contributes to a growing body of evidence that oxidative stress provides a particular strain on cellular protein stability.

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Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response.

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