Fungal Hsp90: A biological transistor that tunes cellular outputs to thermal inputs

1] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
Nature Reviews Microbiology (Impact Factor: 23.57). 09/2012; 10(10):693-704. DOI: 10.1038/nrmicro2875
Source: PubMed


Heat shock protein 90 (HSP90) is an essential, abundant and ubiquitous eukaryotic chaperone that has crucial roles in protein folding and modulates the activities of key regulators. The fungal Hsp90 interactome, which includes numerous client proteins such as receptors, protein kinases and transcription factors, displays a surprisingly high degree of plasticity that depends on environmental conditions. Furthermore, although fungal Hsp90 levels increase following environmental challenges, Hsp90 activity is tightly controlled via post-translational regulation and an autoregulatory loop involving heat shock transcription factor 1 (Hsf1). In this Review, we discuss the roles and regulation of fungal Hsp90. We propose that Hsp90 acts as a biological transistor that modulates the activity of fungal signalling networks in response to environmental cues via this Hsf1-Hsp90 autoregulatory loop.

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    • "In C. albicans, temperature affects the resistance of C. albicans to cell wall stresses but not osmotic stress, whereas Hsp90 depletion affects cell wall biogenesis by impairing the activation of its client proteins Mkc1 and Hog1, as well as Cek1 (Leach et al. 2012). These results indicate that in C. albicans Hsp90 modulates the short-term Hsf1-mediated activation of the classic heat shock response and coordinates this response with the long-term thermal adaptation process via Mkc1-, Hog1-, and Cek1-mediated cell wall remodeling (Leach et al. 2012). In A. fumigatus neither temperature nor sub-inhibitory concentrations of GEL had a dramatic influence on growth (data not shown). "
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    ABSTRACT: Aspergillus fumigatus is a fungal pathogen, which causes several invasive and non-invasive diseases named aspergillosis. This disease is generally regarded as multifactorial considering that several pathogenicity determinants are present during the establishment of this illness. It is necessary to obtain an increased knowledge of how, and which, A. fumigatus signal transduction pathways are engaged in the regulation of these processes. Protein phosphatases are essential to several signal transduction pathways. We identified 32 phosphatase catalytic subunit-encoding genes in A. fumigatus, of which we were able to construct 24 viable deletion mutants. The role of 9 phosphatase mutants in the HOG (High Osmolarity Glycerol response) pathway was evaluated by measuring phosphorylation of the p38 MAPK (SakA) and expression of osmo-dependent genes. We were also able to identify 11 phosphatases involved in iron assimilation, 6 that are related to gliotoxin resistance, and 3 implicated in gliotoxin production. These results present the creation of a fundamental resource for the study of signaling in A. fumigatus and its implications in the regulation of pathogenicity determinants and virulence in this important pathogen. Copyright © 2015 Author et al.
    G3-Genes Genomes Genetics 05/2015; 5(7). DOI:10.1534/g3.115.016766 · 3.20 Impact Factor
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    • "Even though C. albicans is obligately associated with warm-blooded mammals and occupies thermally buffered niches, it has retained the classic heat shock response (22). Indeed, Hsf1 is essential for viability in C. albicans, reflecting the fundamental importance of heat shock adaptation in all organisms (22–24). Our recent exploration of the dynamic regulation of Hsf1 during thermal adaptation has suggested that Hsf1 is activated even during slow thermal transitions such as the increases in temperature suffered by febrile patients (11). "
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    ABSTRACT: Temperature is a ubiquitous environmental variable, which can profoundly influence the physiology of living cells as it changes over time and space. When yeast cells are exposed to a sub lethal heat shock, normal metabolic functions become repressed and the heat shock transcription factor Hsf1 is activated, inducing heat shock proteins (HSPs). Candida albicans, the most prevalent human fungal pathogen, is an opportunistic pathogen that has evolved as a relatively harmless commensal of healthy individuals. Even though C. albicans occupies thermally buffered niches, it has retained the classic heat shock response, activating Hsf1 during slow thermal transitions such as the increases in temperature suffered by febrile patients. However, the mechanism of temperature sensing in fungal pathogens remains enigmatic. Few studies in S. cerevisiae suggest that thermal stress is transduced into a cellular signal at the level of the membrane. In this study, we manipulate the fluidity of C. albicans membrane to dissect mechanisms of temperature sensing. We determined that in response to elevated temperature, levels of the fatty acid desaturase OLE1 decrease. Subsequently, loss of Ole1 triggers expression of the fatty acid synthase FAS2. Furthermore, depletion of Ole1 prevents full activation of Hsf1, thereby reducing HSP expression in response to heat shock. This reduction in Hsf1 activation is attributable to the E3 ubiquitin ligase Rsp5, which regulates OLE1 expression. To our knowledge, this is the first study to define a molecular link between fatty acid synthesis and the heat shock response in the fungal kingdom.
    Eukaryotic Cell 06/2014; 13(8). DOI:10.1128/EC.00138-14 · 3.18 Impact Factor
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    • "GFP green fluorescent protein HSE heat shock element HSP heat shock protein MAPK mitogen-activated protein kinase MAPKK MAP kinase kinase MAPKKK MAP kinase kinase kinase RCS reactive chlorine species RNS reactive nitrogen species ROS reactive oxygen species SAPK stress-activated protein kinase REVIEW The Journal of Experimental Biology (2014) doi:10.1242/jeb.088930 physically with Hsf1 to downregulate the heat shock response in C. albicans (Leach et al., 2012b) (Fig. 1). Significantly, while other conserved stress regulatory circuits have undergone evolutionary rewiring (see below), heat shock regulation has been maintained in C. albicans (Nicholls et al., 2009) despite its obligate association with warm-blooded animals (Odds, 1988). "
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    ABSTRACT: Candida albicans is a major fungal pathogen of humans. This yeast is carried by many individuals as a harmless commensal, but when immune defences are perturbed it causes mucosal infections (thrush). Additionally, when the immune system becomes severely compromised, C. albicans often causes life-threatening systemic infections. A battery of virulence factors and fitness attributes promote the pathogenicity of C. albicans. Fitness attributes include robust responses to local environmental stresses, the inactivation of which attenuates virulence. Stress signalling pathways in C. albicans include evolutionarily conserved modules. However, there has been rewiring of some stress regulatory circuitry such that the roles of a number of regulators in C. albicans have diverged relative to the benign model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. This reflects the specific evolution of C. albicans as an opportunistic pathogen obligately associated with warm-blooded animals, compared with other yeasts that are found across diverse environmental niches. Our understanding of C. albicans stress signalling is based primarily on the in vitro responses of glucose-grown cells to individual stresses. However, in vivo this pathogen occupies complex and dynamic host niches characterised by alternative carbon sources and simultaneous exposure to combinations of stresses (rather than individual stresses). It has become apparent that changes in carbon source strongly influence stress resistance, and that some combinatorial stresses exert non-additive effects upon C. albicans. These effects, which are relevant to fungus-host interactions during disease progression, are mediated by multiple mechanisms that include signalling and chemical crosstalk, stress pathway interference and a biological transistor.
    Journal of Experimental Biology 01/2014; 217(Pt 1):144-55. DOI:10.1242/jeb.088930 · 2.90 Impact Factor
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