Mathematical modeling enlightens the dynamic response of yeast cells to hyperosmotic shock.
Edda Klipp (1), Bodil Nordlander (2), Peter Gennemark (3), Stefan Hohmann (2)
(1) Vertebrate Genomics, Max Planck Institute for Molec, Ihnestr. 73, Berlin, 14195, Germany; (2) Department of Cell and Molecular Biology/Microbiology, Göteborg University, Box 462, S-40530 Göteborg, Sweden; (3) Department of Computer Science and Engineering, Chalmers University of Technology, S-41296 Göteborg, Sweden
Cellular osmoregulation covers active processes to monitor and adjust osmotic pressure and to control cell shape, turgor and water content. We combine the experimental investigation of the cellular response to hyperosmotic shock with a dynamic mathematical model. The model comprises the stimulation of membrane receptors, the subsequent signaling pathway, the activation of gene expression and the adaptation of cellular metabolism to accumulate glycerol, combined with a thermodynamic description of the regulation of volume and osmotic pressure. Model predictions agree well with experimental results obtained under different stress conditions or using certain mutants. Simulations reveal properties of the signaling process and enlighten the roles of the glycerol channel Fps1 in glycerol accumulation and the protein phosphatases in feedback control of the MAP kinase pathway. We show that Fps1 is responsible for the immediate effect on the internal glycerol concentration while the stimulated expression of GPD1 and GPP2 and the resulting increased glycerol production accounts for maintaining a high level of glycerol during growth in high osmolarity. The model implies that downregulation of the HOG pathway is not necessarily dependent on enhanced expression of genes encoding phosphatases but that signal termination is due to glycerol accumulation, cell re-swelling, and turgor increase. This is supported by the fact that the pathway can be fully reactivated by a second osmotic stress.