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new TPGS ambient temperature. This prediction has been confirmed experimentally. For example, when a 30uC37uC heat shock is applied the system recovers rapidly, with Hsf1 phosphorylation returning to basal levels within 20 minutes. After a 30uC42uC heat shock the system recovers after about 2 hours. “2674416 Therefore, the heat shock regulatory network adapts perfectly to changes in ambient temperature. This observation is significant because it accounts for another experimental result that was not initially obvious. Previously we were surprised to find that while Hsf1 is phosphorylated in response to mild heat shocks, Hsf1 is not phosphorylated in C. albicans cells that have adapted to different growth temperatures ranging from 15uC40uC. However, the perfect adaptation displayed by the thermal adaptation system can account for this experimental result. According to the model, Hsf1 is rapidly and transiently activated when cells are adapting to a temperature upshift. However Hsf1 phosphorylation returns to basal levels once this adaptation to the new ambient temperature is complete. Discussion The heat shock response is a fundamentally important adaptive response that is highly conserved across eukaryotic systems. A key function of this response is to maintain protein quality and homeostasis in the face of thermal insults through the induction of genes encoding chaperones and components of the protein degradation machinery. Our current understanding of heat shock adaptation is primarily based on a strong experimental platform that has largely focussed on dramatic and acute heat shocks. In this study we have exploited an integrative systems biology approach with a view to understanding thermal adaptation under conditions that are more relevant physiologically but less tractable experimentally. This represents one of the first applications of mathematical modelling to understand a dynamic adaptive response in a fungal pathogen. Our mathematical model of thermal adaptation was based on a number of assumptions and upon published observations from our own and other laboratories. A previous model focused on the feedback regulatory mechanisms of heat shock proteins on HSF function in mammalian systems. However, these models did not address Hsp90 specifically, although experimental inhibition of Hsp90 has been shown to activate Hsf1 in mammalian cells and yeast. Therefore, our model was based on the hypothesis that an autoregulatory loop involving Hsf1 and Hsp90 lies at the heart of thermal adaptation. Our experimentally verified assumption that Hsp90 is a major player in thermal adaptation does not exclude the possibility that other factors probably contribute to thermal adaptation. Furthermore, our model includes interactions between March 2012 | Volume 7 | Issue 3 | e32467 Autoregulation of Thermal Adaptation Hsf1 and its protein kinase and phosphatase. The identity of the protein kinase that phosphorylate Hsf1 in yeast is not known, and relatively little is known about the signalling cascades that trigger Hsf1 activation. The phosphatase activity appears to be equally important in regulating thermal adaptation, as Hsf1 is rapidly dephosphorylated in C. albicans upon a cold shock. The model accurately predicted numerous molecular behaviours of the thermal adaptation system, suggesting that our underlying hypotheses are valid. Nevertheless, in the future, the boundaries of our model could be extended to include, for example, other molecules that
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