Institute of Bio- und Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, Jülich, 52425, Germany.
LOEWE-Zentrum für Synthetische Mikrobiologie, Philipps-Universität Marburg, Marburg, 35032, Germany.
Mol Microbiol. 2019 May;111(5):1367-1381. doi: 10.1111/mmi.14226. Epub 2019 Mar 22.
Heme is an essential cofactor and alternative iron source for almost all bacterial species but may cause severe toxicity upon elevated levels and consequently, regulatory mechanisms coordinating heme homeostasis represent an important fitness trait. A remarkable scenario is found in several corynebacterial species, e.g. Corynebacterium glutamicum and Corynebacterium diphtheriae, which dedicate two paralogous, heme-responsive two-component systems, HrrSA and ChrSA, to cope with the Janus nature of heme. Here, we combined experimental reporter profiling with a quantitative mathematical model to understand how this particular regulatory network architecture shapes the dynamic response to heme. Our data revealed an instantaneous activation of the detoxification response (hrtBA) upon stimulus perception and we found that kinase activity of both kinases contribute to this fast onset. Furthermore, instant deactivation of the P promoter is achieved by a strong ChrS phosphatase activity upon stimulus decline. While the activation of detoxification response is uncoupled from further factors, heme utilization is additionally governed by the global iron regulator DtxR integrating information on iron availability into the regulatory network. Altogether, our data provide comprehensive insights how TCS cross-regulation and network hierarchy shape the temporal dynamics of detoxification (hrtBA) and utilization (hmuO) as part of a global homeostatic response to heme.
血红素是几乎所有细菌物种的必需辅因子和替代铁源，但在水平升高时可能会引起严重毒性，因此，协调血红素稳态的调节机制代表了一个重要的适应性特征。在几种棒状杆菌物种中发现了一个显著的情况，例如谷氨酸棒状杆菌和白喉棒状杆菌，它们专门为血红素的两面性分配了两个同源的、血红素响应的双组分系统，HrrSA 和 ChrSA，以应对血红素的两面性。在这里，我们将实验报告分析与定量数学模型相结合，以了解这种特殊的调控网络架构如何塑造对血红素的动态响应。我们的数据揭示了在刺激感知时解毒反应（hrtBA）的瞬时激活，并且我们发现两个激酶的激酶活性都有助于这种快速起始。此外，在刺激下降时，ChrS 磷酸酶的强烈活性可立即失活 P 启动子。虽然解毒反应的激活与其他因素脱钩，但血红素的利用还受到全局铁调节剂 DtxR 的控制，该调节剂将铁可用性的信息整合到调控网络中。总的来说，我们的数据提供了全面的见解，即 TCS 交叉调节和网络层次结构如何塑造解毒（hrtBA）和利用（hmuO）的时间动态，作为血红素全局稳态反应的一部分。
