title: Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast.
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.
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany. schaber@med.ovgu.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaber
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Baltanas
authors.forename: Alan
authors.initials: A
authors.lastname: Bush
authors.forename: Edda
authors.initials: E
authors.lastname: Klipp
authors.forename: Alejandro
authors.initials: A
authors.lastname: Colman-Lerner
mesh_terms: D000222:Adaptation, Physiological; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological; D005990:Glycerol / Q000378:metabolism; D006706:Homeostasis; D042541:Intracellular Space / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009997:Osmotic Pressure; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; C069938:SPT2 protein, S cerevisiae; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; D005990:Glycerol