Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response.
Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response.
复制标题
DOI：
10.1128/msystems.00979-20
复制
发表时间：
2021-02-16
期刊：
影响因子：
6.4
通讯作者：
Igoshin OA
中科院分区：
文献类型：
--
作者：
Rao SD;Datta P;Gennaro ML;Igoshin OA
基因调控网络的动态特性被调整以确保细菌的存活。在分枝杆菌中，MprAB-σE网络响应于应激源的存在，例如引起表面应激的表面活性剂。该网络中的正反馈回路先前被预测会导致滞后，即，预应力和无应力细胞对相同应力水平的不同反应。在这里，我们表明，滞后不发生在非致病性的耻垢分枝杆菌，但发生在结核分枝杆菌。然而，在M.结核病与模型预测不一致。为了调和这些观察结果，我们实现了最近提出的压力传感机制，即，释放MprB的抑制复合物与伴侣DnaK的压力暴露后。通过建模和参数拟合，我们证明了这种机制可以准确地描述实验观察。此外，我们预测扰动DnaK表达，可以强烈影响动力学性质。这些扰动的实验与模型预测一致，证实了DnaK在快速和持续反应中的作用。重要性控制分枝杆菌物种应激反应的基因调控网络与使细菌在宿主内休眠的持久性开关有关。然而，开关和应力传感的机械基础还没有完全理解。本文结合定量实验和数学建模，揭示了应力响应的两个主要调控因子--MprAB双组分系统（TCS）和σ因子σ E--之间的相互作用如何影响表面应力网络的动力学性质。结果表明，病原菌M的响应具有滞后性（历史依赖性）。结核表面应力和缺乏滞后的非致病性M。恶臭此外，为了解决滞后的存在和快速激活的响应之间的明显矛盾，我们利用最近提出的伴侣蛋白DnaK在压力传感的作用。这些结果导致了一个新的系统级的细菌应激反应动力学的理解。
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.