Rao Satyajit D, Datta Pratik, Gennaro Maria Laura, Igoshin Oleg A
Department of Bioengineering and Center for Theoretical Biological Physics, Rice University, Houston, Texas, USA.
Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.
mSystems. 2021 Feb 16;6(1):e00979-20. doi: 10.1128/mSystems.00979-20.
Dynamical properties of gene regulatory networks are tuned to ensure bacterial survival. In mycobacteria, the MprAB-σ 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 but does occur in However, the observed rapid temporal response in 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. 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-shape the dynamical properties of the surface stress network. The result show hysteresis (history dependence) in the response of the pathogenic bacterium to surface stress and lack of hysteresis in nonpathogenic 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.
基因调控网络的动力学特性经过调整以确保细菌存活。在分枝杆菌中，MprAB-σ网络会对应激源的存在做出反应，比如导致表面应激的表面活性剂。此前预测该网络中的正反馈回路会导致滞后现象，即预应激和未应激细胞对相同应激源水平的反应不同。在这里，我们表明非致病的[具体菌种未提及]中不会出现滞后现象，但在[具体致病菌种未提及]中会出现。然而，在[具体致病菌种未提及]中观察到的快速时间响应与模型预测不一致。为了协调这些观察结果，我们采用了一种最近提出的应激感应机制，即应激暴露时MprB从与伴侣蛋白DnaK的抑制复合物中释放出来。通过建模和参数拟合，我们证明该机制可以准确描述实验观察结果。此外，我们预测DnaK表达的扰动会强烈影响动力学特性。对这些扰动进行的实验与模型预测相符，证实了DnaK在快速和持续响应中的作用。控制分枝杆菌属物种应激反应的基因调控网络与使细菌在宿主体内进入休眠状态的持久性开关有关。然而，转换和应激感应的机制基础尚未完全理解。在本文中，我们结合定量实验和数学建模，揭示了应激反应的两个主要调节因子——MprAB双组分系统（TCS）和替代西格玛因子σ之间的相互作用如何塑造表面应激网络的动力学特性。结果表明，致病细菌[具体致病菌种未提及]对表面应激的反应存在滞后现象（历史依赖性），而非致病的[具体菌种未提及]则没有。此外，为了解决滞后现象的存在与反应快速激活之间的明显矛盾，我们利用了伴侣蛋白DnaK在应激感应中的最新提出的作用。这些结果带来了对细菌应激反应动力学的全新系统层面理解。
