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

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dc.citation.articleNumbere00979-20en_US
dc.citation.journalTitlemSystemsen_US
dc.citation.volumeNumber6en_US
dc.contributor.authorRao, Satyajit D.en_US
dc.contributor.authorDatta, Pratiken_US
dc.contributor.authorGennaro, Maria Lauraen_US
dc.contributor.authorIgoshin, Oleg A.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2021-04-21T15:46:23Zen_US
dc.date.available2021-04-21T15:46:23Zen_US
dc.date.issued2021en_US
dc.description.abstractDynamical properties of gene regulatory networks are tuned to ensure bacterial survival. In mycobacteria, the MprAB-σE 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 σE—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.en_US
dc.identifier.citationRao, Satyajit D., Datta, Pratik, Gennaro, Maria Laura, et al.. "Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response." <i>mSystems,</i> 6, (2021) American Society for Microbiology: https://doi.org/10.1128/mSystems.00979-20.en_US
dc.identifier.digitalmSystems-2021-Rao-e00979-20en_US
dc.identifier.doihttps://doi.org/10.1128/mSystems.00979-20en_US
dc.identifier.urihttps://hdl.handle.net/1911/110304en_US
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleChaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Responseen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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