Gao Rong, Godfrey Katherine A, Sufian Mahir A, Stock Ann M
Center for Advanced Biotechnology and Medicine, Department of Biochemistry and Molecular Biology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
Center for Advanced Biotechnology and Medicine, Department of Biochemistry and Molecular Biology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
J Bacteriol. 2017 Aug 22;199(18). doi: 10.1128/JB.00390-17. Print 2017 Sep 15.
Fluctuations in nutrient availability often result in recurrent exposures to the same stimulus conditions. The ability to memorize the past event and use the "memory" to make adjustments to current behaviors can lead to a more efficient adaptation to the recurring stimulus. A short-term phenotypic memory can be conferred via carryover of the response proteins to facilitate the recurrent response, but the additional accumulation of response proteins can lead to a deviation from response homeostasis. We used the PhoB/PhoR two-component system (TCS) as a model system to study how cells cope with the recurrence of environmental phosphate (Pi) starvation conditions. We discovered that "memory" of prior Pi starvation can exert distinct effects through two regulatory pathways, the TCS signaling pathway and the stress response pathway. Although carryover of TCS proteins can lead to higher initial levels of transcription factor PhoB and a faster initial response in prestarved cells than in cells not starved, the response enhancement can be overcome by an earlier and greater repression of promoter activity in prestarved cells due to the memory of the stress response. The repression counterbalances the carryover of the response proteins, leading to a homeostatic response whether or not cells are prestimulated. A computational model based on sigma factor competition was developed to understand the memory of stress response and to predict the homeostasis of other PhoB-regulated response proteins. Our insight into the history-dependent PhoBR response may provide a general understanding of how TCSs respond to recurring stimuli and adapt to fluctuating environmental conditions. Bacterial cells in their natural environments experience scenarios that are far more complex than are typically replicated in laboratory experiments. The architectures of signaling systems and the integration of multiple adaptive pathways have evolved to deal with such complexity. In this study, we examined the molecular "memory" that is generated by previous exposure to stimulus. Under our experimental conditions, activating effects of autoregulated two-component signaling and inhibitory effects of the stress response counterbalanced the transcriptional output to approach response homeostasis whether or not cells had been preexposed to stimulus. Modeling allows prediction of response behavior in different scenarios and demonstrates both the robustness of the system output and its sensitivity to historical parameters such as timing and levels of exposure to stimuli.
营养物质可用性的波动常常导致细胞反复暴露于相同的刺激条件下。记住过去事件并利用这种“记忆”来调整当前行为的能力，能够使细胞更有效地适应反复出现的刺激。短期表型记忆可通过响应蛋白的残留来赋予，以促进反复响应，但响应蛋白的额外积累可能导致偏离响应稳态。我们使用PhoB/PhoR双组分系统（TCS）作为模型系统，来研究细胞如何应对环境磷酸盐（Pi）饥饿条件的反复出现。我们发现，先前Pi饥饿的“记忆”可通过两条调节途径发挥不同作用，即TCS信号通路和应激反应通路。尽管TCS蛋白的残留可导致转录因子PhoB的初始水平更高，且与未饥饿的细胞相比，预饥饿细胞的初始反应更快，但由于应激反应的记忆，预饥饿细胞中启动子活性更早且更强的抑制作用可抵消这种反应增强。这种抑制作用平衡了响应蛋白的残留，无论细胞是否受到预刺激，都能导致稳态响应。我们开发了一个基于σ因子竞争的计算模型，以理解应激反应的记忆，并预测其他PhoB调节的响应蛋白的稳态。我们对依赖历史的PhoBR反应的深入了解，可能有助于全面理解TCS如何应对反复出现的刺激并适应波动的环境条件。细菌细胞在自然环境中所经历的情况远比实验室实验中通常模拟的情况复杂得多。信号系统的架构以及多种适应性途径的整合已经进化以应对这种复杂性。在本研究中，我们研究了先前暴露于刺激所产生的分子“记忆”。在我们的实验条件下，无论细胞是否预先暴露于刺激，自调节双组分信号的激活作用和应激反应的抑制作用都会平衡转录输出，以接近响应稳态。建模可以预测不同情况下的反应行为，并证明系统输出的稳健性及其对诸如刺激暴露的时间和水平等历史参数的敏感性。
