Open Access Research article

A systems biology analysis of long and short-term memories of osmotic stress adaptation in fungi

Tao You17, Piers Ingram2, Mette D Jacobsen3, Emily Cook4, Andrew McDonagh5, Thomas Thorne6, Megan D Lenardon3, Alessandro PS de Moura1, M Carmen Romano1, Marco Thiel1, Michael Stumpf6, Neil AR Gow3, Ken Haynes4, Celso Grebogi1, Jaroslav Stark8 and Alistair JP Brown3*

Author Affiliations

1 Institute for Complex Systems and Mathematical Biology, School of Natural and Computing Sciences, University of Aberdeen, Old Aberdeen, Aberdeen, AB24 3UE, UK

2 Department of Mathematics, Imperial College London, London, SW7 2AZ, UK

3 School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Aberdeen, AB25 2ZD, UK

4 Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK

5 Department of Microbiology, Imperial College London, The Flowers Building, London, SW7 2AZ, UK

6 Centre for Bioinformatics, Division of Molecular Biosciences, Wolfson Building, Imperial College London, South Kensington Campus, London, SW7 2AY, UK

7 Computational Biology, AstraZeneca, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK

8 Formally of the Department of Mathematics, Imperial College London, London, SW7 2AZ, UK

For all author emails, please log on.

BMC Research Notes 2012, 5:258  doi:10.1186/1756-0500-5-258

Published: 25 May 2012



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.