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Integrative model of the response of yeast to osmotic shock

Nature Biotechnology volume 23, pages 975–982 (2005)Cite this article

A Corrigendum to this article was published on 01 October 2006

Abstract

Integration of experimental studies with mathematical modeling allows insight into systems properties, prediction of perturbation effects and generation of hypotheses for further research. We present a comprehensive mathematical description of the cellular response of yeast to hyperosmotic shock. The model integrates a biochemical reaction network comprising receptor stimulation, mitogen-activated protein kinase cascade dynamics, activation of gene expression and adaptation of cellular metabolism with a thermodynamic description of volume regulation and osmotic pressure. Simulations agree well with experimental results obtained under different stress conditions or with specific mutants. The model is predictive since it suggests previously unrecognized features of the system with respect to osmolyte accumulation and feedback control, as confirmed with experiments. The mathematical description presented is a valuable tool for future studies on osmoregulation in yeast and—with appropriate modifications—other organisms. It also serves as a starting point for a comprehensive description of cellular signaling.

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Figure 1: Overview of the response of yeast to hyperosmotic stress.
Figure 2: Steady states of the phosphorelay module and the metabolism module.
Figure 3: Time courses for key molecules of the osmotic shock response monitored in the standard experiment, that is, a single osmotic shock with 0.5 M NaCl at time 0 min.
Figure 4: Test of model predictions and effects of system perturbations.
Figure 5: Test of model predictions for the experimental scenario of two subsequent osmotic shock treatments at various time points.

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Acknowledgements

E.K. is supported by the Berlin Center of Genome Based Bioinformatics (BCB), financed by the German Federal Ministry for Education and Research (BMBF, grant 031U109C). B.N. and P.G. are PhD students of the National Research School for Genomics and Bioinformatics, Göteborg, supported by the Swedish Ministry for Education and Research. S.H. holds a research position of the Swedish Research Council. Research in his lab is supported by the European Commission (contracts QLK3-CT2000-00778 and QLK1-CT2001-01066) and the Human Frontier Science Program. Systems Biology of yeast osmoregulation is supported by the European Commission (the QUASI project, contract LSHG-CT2003-503230 to S.H. and E.K.).

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Author notes

  1. Edda Klipp and Bodil Nordlander: These authors contributed equally to this work.

Authors and Affiliations

  1. Berlin Center for Genome Based Bioinformatics (BCB), Max-Planck Institute for Molecular Genetics, Dept. Vertebrate Genomics, Ihnestr. 73, Berlin, 14195, Germany

    Edda Klipp

  2. Department of Cell and Molecular Biology/Microbiology, Göteborg University, Box 462, Göteborg, S-40530, Sweden

    Bodil Nordlander & Stefan Hohmann

  3. Humboldt University Berlin, Institute for Biology, Invalidenstr. 43, Berlin, 10115, Germany

    Roland Krüger

  4. Department of Computer Science and Engineering, Chalmers University of Technology, Göteborg, S-41296, Sweden

    Peter Gennemark

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  1. Edda Klipp
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Correspondence to Edda Klipp or Stefan Hohmann.

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Supplementary information

Supplementary Fig. 1

Standard experiment (one single osmotic shock in wild type cells with 0.5 M NaCl at time zero) used for parameter determination. (PDF 24 kb)

Supplementary Fig. 2

Parameter dependence of the behavior of the MAPK cascade. (PDF 23 kb)

Supplementary Fig. 3

Sensitivity S of the Euclidean distance D between experimental data and simulations with respect to parameter variation. (PDF 36 kb)

Supplementary Fig. 4

Dependence of characteristic system features on parameter values. (PDF 44 kb)

Supplementary Fig. 5

Simulation of osmotic shocks with increasing level of NaCl. (PDF 35 kb)

Supplementary Fig. 6

Open Fps1. (PDF 18 kb)

Supplementary Fig. 7

Yeast cells overproducing glycerol. (PDF 24 kb)

Supplementary Fig. 8

Overproduction of protein phosphatase Ptp2 in wild type cells and cells with unregulated Fps1. (PDF 91 kb)

Supplementary Fig. 9

Profile of intracellular glycerol levels in wild type cells. (PDF 18 kb)

Supplementary Fig. 10

Simulations of enhanced expression of activated alleles of Ssk2 (dark dashed lines) and Hog1 (gray dashed lines). (PDF 15 kb)

Supplementary Table 1

Equations governing the dynamics of the phosphorelay module. (PDF 30 kb)

Supplementary Table 2

Equations governing the dynamics of the MAP kinase cascade. (PDF 36 kb)

Supplementary Table 3

Equations governing the dynamics of transcription and translation. (PDF 26 kb)

Supplementary Table 4

Equations governing the dynamics of the carbohydrate metabolism. (PDF 46 kb)

Supplementary Table 5

Set of equations governing the changes of volume and osmotic pressure. (PDF 60 kb)

Supplementary Table 6

Integrative model of the response of yeast cells to osmotic shock. (PDF 65 kb)

Supplementary Data (PDF 76 kb)

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Klipp, E., Nordlander, B., Krüger, R. et al. Integrative model of the response of yeast to osmotic shock. Nat Biotechnol 23, 975–982 (2005). https://doi.org/10.1038/nbt1114

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