Abstract：
The inherent stochasticity of metabolism raises a critical question for understanding homeostasis: are cellular processes regulated in response to internal fluctuations? Here, we show that, in E. coli cells under constant external conditions, catabolic enzyme expression continuously responds to metabolic fluctuations. The underlying regulatory feedback is enabled by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) system, which controls catabolic enzyme expression based on metabolite concentrations. Using single-cell microscopy, genetic constructs in which this feedback is disabled, and mathematical modeling, we show how fluctuations circulate through the metabolic and genetic network at sub-cell-cycle timescales. Modeling identifies four noise propagation modes, including one specific to CRP regulation. Together, these modes correctly predict noise circulation at perturbed cAMP levels. The cAMP-CRP system may thus have evolved to control internal metabolic fluctuations in addition to external growth conditions. We conjecture that second messengers may more broadly function to achieve cellular homeostasis.
摘要：
新陈代谢的内在随机性为理解稳态提出了一个关键问题：细胞过程是否因内部波动而受到调节？我们证明，在恒定的外部条件下，在大肠杆菌细胞中，分解代谢酶表达连续响应代谢波动。潜在的调节反馈是通过环AMP（cAMP）和cAMP受体蛋白（CRP）系统实现的，根据代谢物浓度控制分解代谢酶的表达。使用单细胞显微镜，这种反馈被禁用的遗传结构，和数学建模，我们展示了亚细胞周期时间尺度的波动如何在代谢和遗传网络中循环。建模确定了四种噪声传播模式，包括一个特定的CRP调节。一起,这些模式正确地预测干扰cAMP水平的噪声循环。因此，除了外部生长条件外，cAMP-CRP系统可能已经进化为控制内部代谢波动。我们推测第二信使可能更广泛地发挥作用以实现细胞稳态。
