You Tao, Ingram Piers, Jacobsen Mette D, Cook Emily, McDonagh Andrew, Thorne Thomas, Lenardon Megan D, de Moura Alessandro P S, Romano M Carmen, Thiel Marco, Stumpf Michael, Gow Neil A R, Haynes Ken, Grebogi Celso, Stark Jaroslav, Brown Alistair J P
Institute for Complex Systems and Mathematical Biology, School of Natural and Computing Sciences, University of Aberdeen, Aberdeen, UK.
BMC Res Notes. 2012 May 25;5:258. doi: 10.1186/1756-0500-5-258.
Saccharomyces cerevisiae senses hyperosmotic conditions via the HOG signaling network that activates the stress-activated protein kinase, Hog1, and modulates metabolic fluxes and gene expression to generate appropriate adaptive responses. The integral control mechanism by which Hog1 modulates glycerol production remains uncharacterized. An additional Hog1-independent mechanism retains intracellular glycerol for adaptation. Candida albicans also adapts to hyperosmolarity via a HOG signaling network. However, it remains unknown whether Hog1 exerts integral or proportional control over glycerol production in C. albicans.
We combined modeling and experimental approaches to study osmotic stress responses in S. cerevisiae and C. albicans. We propose a simple ordinary differential equation (ODE) model that highlights the integral control that Hog1 exerts over glycerol biosynthesis in these species. If integral control arises from a separation of time scales (i.e. rapid HOG activation of glycerol production capacity which decays slowly under hyperosmotic conditions), then the model predicts that glycerol production rates elevate upon adaptation to a first stress and this makes the cell adapts faster to a second hyperosmotic stress. It appears as if the cell is able to remember the stress history that is longer than the timescale of signal transduction. This is termed the long-term stress memory. Our experimental data verify this. Like S. cerevisiae, C. albicans mimimizes glycerol efflux during adaptation to hyperosmolarity. Also, transient activation of intermediate kinases in the HOG pathway results in a short-term memory in the signaling pathway. This determines the amplitude of Hog1 phosphorylation under a periodic sequence of stress and non-stressed intervals. Our model suggests that the long-term memory also affects the way a cell responds to periodic stress conditions. Hence, during osmohomeostasis, short-term memory is dependent upon long-term memory. This is relevant in the context of fungal responses to dynamic and changing environments.
Our experiments and modeling have provided an example of identifying integral control that arises from time-scale separation in different processes, which is an important functional module in various contexts.
酿酒酵母通过HOG信号网络感知高渗条件，该网络激活应激激活蛋白激酶Hog1，并调节代谢通量和基因表达以产生适当的适应性反应。Hog1调节甘油生成的整体控制机制仍未明确。另一种不依赖Hog1的机制可保留细胞内甘油以实现适应。白色念珠菌也通过HOG信号网络适应高渗环境。然而，Hog1是否对白色念珠菌的甘油生成发挥整体或比例控制作用仍不清楚。
我们结合建模和实验方法研究酿酒酵母和白色念珠菌的渗透应激反应。我们提出了一个简单的常微分方程（ODE）模型，该模型突出了Hog1对这些物种中甘油生物合成的整体控制。如果整体控制源于时间尺度的分离（即甘油生产能力的快速HOG激活，在高渗条件下缓慢衰减），那么该模型预测，细胞在适应第一次应激时甘油生成速率会升高，这使得细胞能更快地适应第二次高渗应激。就好像细胞能够记住比信号转导时间尺度更长的应激历史。这被称为长期应激记忆。我们的实验数据证实了这一点。与酿酒酵母一样，白色念珠菌在适应高渗环境时会尽量减少甘油外流。此外，HOG途径中中间激酶的瞬时激活会导致信号通路中的短期记忆。这决定了在应激和非应激间隔的周期性序列下Hog1磷酸化的幅度。我们的模型表明，长期记忆也会影响细胞对周期性应激条件的反应方式。因此，在渗透稳态过程中，短期记忆依赖于长期记忆。这在真菌对动态变化环境的反应背景下具有重要意义。
我们的实验和建模提供了一个识别源于不同过程中时间尺度分离的整体控制的例子，这是各种情况下的一个重要功能模块。
