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 foreukaryotes. We used an unprecedented amount of data to parameterise 192 models capturingdifferent hypotheses about molecular mechanisms underlying osmo-adaptation and selected a bestapproximating 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 nontranscriptionalHog1-mediated activation of glycerol production, (ii) the transcriptional responseserves to maintain an increased steady-state glycerol production with lowsteady-state Hog1 activity,and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves tostabilise adaptation response. The best approximating model also indicated that homoeostaticadaptive systems with two parallel redundant signalling branches show a more robust and fasterresponse than single-branch systems. We corroborated this notion to a large extent by dedicatedmeasurements of volume recovery in single cells. Our study also demonstrates that systematicallytesting a model ensemble against data has the potential to achieve a better and unbiasedunderstanding of molecular mechanisms.