Abstract
Yeast cells are able to tolerate and adapt to a variety of environmental stresses. An essential aspect of stress adaptation is the regulation of monovalent ion concentrations. Ion regulation determines many fundamental physiological parameters, such as cell volume, membrane potential, and intracellular pH. It is achieved through the concerted activities of multiple cellular components, including ion transporters and signaling molecules, on both short and long time scales. Although each component has been studied in detail previously, it remains unclear how the physiological parameters are maintained and regulated by the concerted action of all components under a diverse range of stress conditions. In this study, we have constructed an integrated mathematical model of ion regulation in Saccharomyces cerevisiae to understand this coordinated adaptation process. Using this model, we first predict that the interaction between phosphorylated Hog1p and Tok1p at the plasma membrane inhibits Tok1p activity and consequently reduces Na+ influx under NaCl stress. We further characterize the impacts of NaCl, sorbitol, KCl and alkaline pH stresses on the cellular physiology and the differences between the cellular responses to these stresses. We predict that the calcineurin pathway is essential for maintaining a non-toxic level of intracellular Na+ in the long-term adaptation to NaCl stress, but that its activation is not required for maintaining a low level of Na+ under other stresses investigated. We provide evidence that, in addition to extrusion of toxic ions, Ena1p plays an important role, in some cases alongside Nha1p, in re-establishing membrane potential after stress perturbation. To conclude, this model serves as a powerful tool for both understanding the complex system-level properties of the highly coordinated adaptation process and generating further hypotheses for experimental investigation.
Highlights
A feature of fungal physiology is the ability to adapt successfully to a variety of environmental perturbations, including ionic [1], osmotic [2] and pH stress [3]
Ion regulation is fundamental to cell physiology
A coherent understanding of the coordinated adaptation process is lacking. We address this gap by constructing a mathematical model that integrates the characteristics of the ion transporters, regulatory molecules, signaling pathways and changes in cell volume
Summary
A feature of fungal physiology is the ability to adapt successfully to a variety of environmental perturbations, including ionic [1], osmotic [2] and pH stress [3] All of these stresses have a substantial impact on intracellular K+/Na+ concentrations and other important physiological parameters of the cell such as cell volume, plasma membrane potential and intracellular pH [4]. One of the key aspects of cellular adaptation to environmental stresses is the maintenance of these parameters within a narrow range This is achieved through the orchestrated activity of monovalent ion transporters, regulatory enzymes, signaling pathways and cellular osmolyte metabolism (see Ref. 5 for a comprehensive review)
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