These proteins function in the synthesis, folding, maturation, trafficking and degradation of proteins, and are essential for protection against

ance is abrogated both by Hsp90 inhibitors ” and by elevated temperatures equivalent to those in febrile 11753686” patients. Fourth, C. albicans heat shock proteins are immunogenic, thereby directly affecting host-pathogen interactions during infection. Finally, autoantibodies against Hsp90 are immunoprotective against C. albicans infections. Taken together, the heat shock response of fungal pathogens is of fundamental importance because it is essential for virulence, and because heat shock proteins represent targets for novel therapeutic strategies. Autoregulation of Thermal Adaptation The exact mechanisms by which thermal adaptation is regulated in eukaryotic cells have been extensively studied, but are still not yet fully understood. When human cells are exposed to heat or a chemical stress, protein unfolding increases, and nonnative proteins begin to accumulate. These non-native proteins are believed to compete with HSF1 for binding to Hsp90, resulting in an increase in unbound HSF1 molecules which rapidly trimerize. In yeast, when cells are exposed to an acute thermal stress, proteins unfold, the heat shock transcription factor becomes activated by phosphorylation, and this induces the expression of heat shock genes. However, key questions remain unanswered in fungi. For example, do heat shock proteins play a role in regulating the heat shock response, for instance possibly by down-regulating Hsf1 following stress adaptation Almost three decades ago, Lindquist and Didomenico et al. postulated that feedback components exist to down-regulate the heat shock response. Initially, Hsp70 was proposed to be a key repressor of Hsf1 activation, but later evidence indicated that Hsp70 is in fact a prerequisite for Hsp90-dependent functions. Indeed, a role for Hsp90 in Hsf1 repression was suggested following the observation that pharmacological inhibition of Hsp90 correlates with HSF1 activation in mammalian cells. Zou and colleagues demonstrated that HSF1 can be cross-linked to Hsp90 in unstressed HeLa cells, suggesting that HSF1 might interact with Hsp90. Additionally, the trimeric form of human HSF1 has been shown to associate with an Hsp90immunophilin-p23 complex, and this is thought to repress HSF1 transcriptional activity. Furthermore, HSP90 modulates HSF1 regulation in Xenopus oocytes. In yeast, mutations that interfere with Hsp90 function have been shown to derepress the expression of Hsf1-dependent reporter genes in S. order GW 501516 cerevisiae. These data infer the existence of an autoregulatory loop in yeast, whereby Hsf1 activates HSP90 expression, and then Hsp90 downregulates Hsf1 activity. How could this autoregulatory loop control the dynamics of heat shock adaptation over time The functionality of biological systems depends upon both negative and positive feedback loops, such that system inputs reinforce or oppose the system output, respectively. Systems biology approaches are being increasingly utilised as a tool to examine the functionality, behaviour and dynamic properties of complex biological systems. However, despite the fundamental importance of heat shock regulation, the application of mathematical modelling to this adaptive response has been very limited. A few studies have examined the robustness of bacterial heat shock systems, which involve the transcriptional control of heat shock functions by the sigma factor s32. Also, there has been minimal modelling of heat shock systems in eukaryotic cells. Rieger and co-workers examined the regulation