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2 Publications visible to you, out of a total of 2
Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast

Abstract (Expand)

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: J. Schaber, R. Baltanas, A. Bush, E. Klipp, A. Colman-Lerner

Date Published: 15th Nov 2012

Publication Type: Not specified

Nested autoinhibitory feedbacks alter the resistance of homeostatic adaptive biochemical networks

Abstract (Expand)

Negative feedback control is a ubiquitous feature of biochemical systems, as is time delay between a signal and its response. Negative feedback in conjunction with time delay can lead to oscillations. … In a cellular context, it might be beneficial to mitigate oscillatory behaviour to avoid recurring stress situations. This can be achieved by increasing the distance between the parameters of the system and certain thresholds, beyond which oscillations occur. This distance has been termed resistance. Here, we prove that in a generic three-dimensional negative feedback system the resistance of the system is modified by nested autoinhibitory feedbacks. Our system features negative feedbacks through both input-inhibition as well as output-activation, a signalling component with mass conservation and perfect adaptation. We show that these features render the system applicable to biological data, exemplified by the high osmolarity glycerol system in yeast and the mammalian p53 system. Output-activation is better supported by data than input-inhibition and also shows distinguished properties with respect to the system's stimulus. Our general approach might be useful in designing synthetic systems in which oscillations can be tuned by synthetic autoinhibitory feedbacks.

Authors: J. Schaber, A. Lapytsko, D. Flockerzi

Date Published: No date defined

Publication Type: Not specified

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