Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast

Molecular Systems Biology

Jörg Schaber¹  Rodrigo Baltanas²  Alan Bush²  Edda Klipp³ 

[1] Institute for Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany;Department of Physiology, Molecular and Cellular Biology, Instituto de Fisiologia, Biologia Molecular y Neurosciencias, Consejo Nacional de Investigaciones Científicas y Técnicas y Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;Theoretical Biophysics, Department of Biology, Humboldt University, Berlin, Germany

关键词: adaptation;    ensemble modeling;    Hopf bifurcation;    model discrimination;    osmotic stress;   

DOI  :  10.1038/msb.2012.53

来源: Wiley

【 摘 要 】

Abstract

The high osmolarity glycerol (HOG) pathway in yeast serves as a prototype signalling system for eukaryotes. We used an unprecedented amount of data to parameterise 192 models capturing different hypotheses about molecular mechanisms underlying osmo-adaptation and selected a best approximating model. This model implied novel mechanisms regulating osmo-adaptation in yeast. The model suggested that (i) the main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production, (ii) the transcriptional response serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity, and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves to stabilise adaptation response. The best approximating model also indicated that homoeostatic adaptive systems with two parallel redundant signalling branches show a more robust and faster response than single-branch systems. We corroborated this notion to a large extent by dedicated measurements of volume recovery in single cells. Our study also demonstrates that systematically testing a model ensemble against data has the potential to achieve a better and unbiased understanding of molecular mechanisms.

Synopsis

Ensemble modelling is used to study the yeast high osmolarity glycerol (HOG) pathway, a prototype for eukaryotic mitogen-activated kinase signalling systems. The best fit model provides new insights into the function of this system, some of which are then experimentally validated.

• The main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production.
• The transcriptional response rather serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity after adaptation.
• A fast negative feedback of activated Hog1 on the upstream signalling branches serves to stabilise the adaptation response by preventing oscillatory behaviour.
• Two parallel redundant signalling branches elicit a more robust and swifter adaptation than a single branch alone, at least for low osmotic shock. This notion could be corroborated by dedicated measurements of single-cell volume recovery for the wild-type and single-branch mutants.

【 授权许可】

CC BY-NC-SA   
Copyright © 2012 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.