Abstract
Thermal adaptation is essential in all organisms. In yeasts, the heat shock response is commanded by the heat shock transcription factor Hsf1. Here we have integrated unbiased genetic screens with directed molecular dissection to demonstrate that multiple signalling cascades contribute to thermal adaptation in the pathogenic yeast Candida albicans. We show that the molecular chaperone heat shock protein 90 (Hsp90) interacts with and down-regulates Hsf1 thereby modulating short term thermal adaptation. In the longer term, thermal adaptation depends on key MAP kinase signalling pathways that are associated with cell wall remodelling: the Hog1, Mkc1 and Cek1 pathways. We demonstrate that these pathways are differentially activated and display cross talk during heat shock. As a result ambient temperature significantly affects the resistance of C. albicans cells to cell wall stresses (Calcofluor White and Congo Red), but not osmotic stress (NaCl). We also show that the inactivation of MAP kinase signalling disrupts this cross talk between thermal and cell wall adaptation. Critically, Hsp90 coordinates this cross talk. Genetic and pharmacological inhibition of Hsp90 disrupts the Hsf1-Hsp90 regulatory circuit thereby disturbing HSP gene regulation and reducing the resistance of C. albicans to proteotoxic stresses. Hsp90 depletion also affects cell wall biogenesis by impairing the activation of its client proteins Mkc1 and Hog1, as well as Cek1, which we implicate as a new Hsp90 client in this study. Therefore Hsp90 modulates the short term Hsf1-mediated activation of the classic heat shock response, coordinating this response with long term thermal adaptation via Mkc1- Hog1- and Cek1-mediated cell wall remodelling.
Highlights
Microorganisms inhabit dynamic environments and are continually challenged with environmental stimuli and stresses
heat shock protein 90 (Hsp90) negatively regulates Hsf1 An autoregulatory loop, whereby Hsf1 activates HSP90 expression and Hsp90 interacts with and down-regulates Hsf1, is thought to lie at the heart of heat shock adaptation in fungi. This presumption provided the basis for mathematical modelling of thermal adaptation in C. albicans [49], but had not been confirmed experimentally. If this presumption is true, one would expect that inhibition of Hsp90, or Hsp90 depletion would lead to Hsf1 activation [49]
We examined the impact of the Hsp90 inhibitors, radicicol and geldanamycin [70,71], upon Hsf1 phosphorylation
Summary
Microorganisms inhabit dynamic environments and are continually challenged with environmental stimuli and stresses. The emergent paradigm is that cells react to environmental changes via a sense and respond logic: they continuously monitor their environment, and upon encountering a stimulus, mount a cellular response [5]. This is achieved through diverse signalling pathways that drive physiological adaptation to a myriad of environmental stresses that include temperature fluctuations, osmotic, oxidative and weak acid stresses, as well as nutrient limitation [6,7]. The core transcriptional responses of S. cerevisiae, S. pombe and C. glabrata involve the activation of common sets of stress genes by one particular stress that promote cross-protection to diverse stresses [2,15,16]. In S. cerevisiae and C. glabrata, this core transcriptional response and stress cross-protection are Author Summary
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