Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response

ABSTRACT Dynamical 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 hys...

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Autores principales:	Satyajit D. Rao, Pratik Datta, Maria Laura Gennaro, Oleg A. Igoshin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Mycobacterium tuberculosis chaperones mathematical modeling sigma factors stress response two-component regulatory systems Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e83c4c1c519741afadfbad51385aedfc
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spelling	oai:doaj.org-article:e83c4c1c519741afadfbad51385aedfc2021-12-02T19:36:37ZChaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response10.1128/mSystems.00979-202379-5077https://doaj.org/article/e83c4c1c519741afadfbad51385aedfc2021-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00979-20https://doaj.org/toc/2379-5077ABSTRACT Dynamical 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.Satyajit D. RaoPratik DattaMaria Laura GennaroOleg A. IgoshinAmerican Society for MicrobiologyarticleMycobacterium tuberculosischaperonesmathematical modelingsigma factorsstress responsetwo-component regulatory systemsMicrobiologyQR1-502ENmSystems, Vol 6, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis chaperones mathematical modeling sigma factors stress response two-component regulatory systems Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis chaperones mathematical modeling sigma factors stress response two-component regulatory systems Microbiology QR1-502 Satyajit D. Rao Pratik Datta Maria Laura Gennaro Oleg A. Igoshin Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response
description	ABSTRACT Dynamical 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.
format	article
author	Satyajit D. Rao Pratik Datta Maria Laura Gennaro Oleg A. Igoshin
author_facet	Satyajit D. Rao Pratik Datta Maria Laura Gennaro Oleg A. Igoshin
author_sort	Satyajit D. Rao
title	Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response
title_short	Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response
title_full	Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response
title_fullStr	Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response
title_full_unstemmed	Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response
title_sort	chaperone-mediated stress sensing in <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> enables fast activation and sustained response
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/e83c4c1c519741afadfbad51385aedfc
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Chaperone-Mediated Stress Sensing in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Enables Fast Activation and Sustained Response

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