Department of Energy, Environmental & Chemical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.
Warwick Integrative Synthetic Biology Centre & School of Engineering, University of Warwick, Coventry, United Kingdom.
mBio. 2020 Mar 17;11(2):e03112-19. doi: 10.1128/mBio.03112-19.
Microbes adapt their metabolism to take advantage of nutrients in their environment. Such adaptations control specific metabolic pathways to match energetic demands with nutrient availability. Upon depletion of nutrients, rapid pathway recovery is key to release cellular resources required for survival under the new nutritional conditions. Yet, little is known about the regulatory strategies that microbes employ to accelerate pathway recovery in response to nutrient depletion. Using the fatty acid catabolic pathway in , here, we show that fast recovery can be achieved by rapid release of a transcriptional regulator from a metabolite-sequestered complex. With a combination of mathematical modeling and experiments, we show that recovery dynamics depend critically on the rate of metabolite consumption and the exposure time to nutrients. We constructed strains with rewired transcriptional regulatory architectures that highlight the metabolic benefits of negative autoregulation over constitutive and positive autoregulation. Our results have wide-ranging implications for our understanding of metabolic adaptations, as well as for guiding the design of gene circuitry for synthetic biology and metabolic engineering. Rapid metabolic recovery during nutrient shift is critical to microbial survival, cell fitness, and competition among microbiota, yet little is known about the regulatory mechanisms of rapid metabolic recovery. This work demonstrates a previously unknown mechanism where rapid release of a transcriptional regulator from a metabolite-sequestered complex enables fast recovery to nutrient depletion. The work identified key regulatory architectures and parameters that control the speed of recovery, with wide-ranging implications for the understanding of metabolic adaptations as well as synthetic biology and metabolic engineering.
微生物会调整其代谢方式以利用环境中的营养物质。这些适应机制控制着特定的代谢途径，使能量需求与营养物质供应相匹配。在营养物质耗尽后，快速恢复途径是释放细胞资源以适应新营养条件的关键。然而，对于微生物在营养物质耗尽时采用何种调控策略来加速途径恢复，目前还知之甚少。本研究以脂肪酸分解代谢途径为例，揭示了微生物可以通过将转录调控因子从代谢物隔离复合物中快速释放，实现快速恢复。通过数学建模和实验相结合的方法，我们发现恢复动力学取决于代谢物消耗速率和暴露于营养物质的时间。我们构建了具有重新布线转录调控架构的菌株，突出了负反馈调控相对于组成型和正反馈调控在代谢方面的优势。我们的研究结果对于理解代谢适应机制以及指导合成生物学和代谢工程中的基因电路设计具有广泛的意义。在营养物质转变过程中快速恢复代谢对于微生物的生存、细胞适应性和微生物群落的竞争至关重要，但对于快速代谢恢复的调控机制却知之甚少。本研究揭示了一种以前未知的机制，即转录调控因子从代谢物隔离复合物中的快速释放，从而实现对营养物质耗尽的快速恢复。该研究确定了控制恢复速度的关键调控架构和参数，对于理解代谢适应以及合成生物学和代谢工程具有广泛的意义。
