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Cited by 107Heat shock proteins researchFungal and yeast genetics researchBacterial Genetics and Biotechnology

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

Open access
Leach, Michelle D., Klipp, Edda, Cowen, Leah E., Brown, Alistair J. P.·2012·Nature Reviews Microbiology
DOI 10.1038/nrmicro2875PMC PMC3660702
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Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that fungal Hsp90 acts as a biological transistor, tuning cellular signalling outputs to thermal and other proteotoxic inputs via an Hsf1–Hsp90 autoregulatory loop. It synthesizes evidence that the Hsp90 interactome is large, environmentally plastic, and enriched for kinases, phosphatases, and transcription factors.

Key findings

  • The fungal Hsp90 interactome is large, comprising about 10% of the proteome, and is enriched for regulators of growth, cell division, environmental adaptation, and development; major client categories include protein kinases/phosphatases and transcription factors.
  • The Hsp90 interactome displays input-dependent plasticity: for example, more protein kinases appear in the *C. albicans* Hsp90 interactome at 37°C than at 30°C, and cell wall stress strengthens Slt2–Hsp90 interactions in *S. cerevisiae*.
  • Hsp90 activity is regulated at multiple levels, including Hsf1-dependent transcription, post-transcriptional control, post-translational modification, and co-chaperones; yeast Hsp90 hydrolyses ATP every 1–2 minutes.
  • Hsp90 can act as an evolutionary capacitor and potentiator, and one *S. cerevisiae* study found Hsp90 influences approximately 20% of natural genetic variation, but this review focuses on its cellular-timescale role as a transistor.

Methods

  • This is a narrative review; no primary experimental methods are reported.
  • It synthesizes published molecular, genetic, genomic, proteomic, and mathematical modelling studies on fungal Hsp90, including data from *S. cerevisiae*, *S. pombe*, and *C. albicans*.
  • It uses a conceptual model of a simple Hsp90 interactome to argue that changes in Hsp90 abundance, client affinity, relative concentrations, and on/off rates can shift signalling pathway activity.

Limitations

  • Stated: the authors note that understanding Hsp90 as a cellular transistor remains a major challenge and requires high-throughput biochemical, biophysical, and mathematical tools to define short-term dynamism and long-term plasticity of the Hsp90 interactome.
  • Stated: most genome-wide Hsp90 screens have been performed under steady-state conditions, so the true plasticity of the interactome is likely best observed under transient conditions.
  • Evident from the text: several key claims rely on unpublished observations (Leach et al., unpublished), and the review itself presents no new primary data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrmicro2875

Cites

145 of 145 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 123 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Hsp90 levels increase following environmental challenges.

    “Furthermore, although Hsp90 levels increase following environmental challenges, Hsp90 activity is tightly controlled via post-translational regulation and an autoregulatory loop involving the heat shock transcription factor, Hsf1.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [10] Nicholls, S., Leach, M. D., Priest, C. L. & Brown, A. J. Role of the heat shock transcription factor, Hsf1, in a major fungal pathogen that is obligately associated with warm-blooded animals. Mol. Microbiol. 74, 844–861 (2009). source

      Not checked in the free run.

    • cites [15] Swoboda, R. K. et al. Structure and regulation of the HSP90 gene from the pathogenic fungus Candida albicans. Infect. Immun. 63, 4506–4514 (1995). source

      Not checked in the free run.

    • cites [32] Chen, D. et al. Global transcriptional responses of fission yeast to environmental stress. Mol. Biol. Cell 14, 214–229 (2003). source

      Not checked in the free run.

    • cites [33] Steen, B. R. et al. Cryptococcus neoformans gene expression during experimental cryptococcal meningitis. Eukaryot. Cell 2, 1336–1349 (2003). source

      Not checked in the free run.

    • cites [34] Albrecht, D., Guthke, R., Brakhage, A. A. & Kniemeyer, O. Integrative analysis of the heat shock response in Aspergillus fumigatus. BMC Genomics 11, 32 (2010). source

      Not checked in the free run.

    • cites [35] Minchiotti, G., Gargano, S. & Maresca, B. The intron-containing hsp82 gene of the dimorphic pathogenic fungus Histoplasma capsulatum is properly spliced in severe heat shock conditions. Mol. Cell. Biol. 11, 5624–5630 (1991). source

      Not checked in the free run.

  • Premisecitation

    The ATPase cycle is relatively slow, yeast Hsp90 hydrolysing an ATP molecule every 1-2 minutes.

    “The ATPase cycle is relatively slow, yeast Hsp90 hydrolysing an ATP molecule every 1-2 minutes28,29.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Panaretou, B. et al. ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J. 17, 4829–4836 (1998). source

      Not checked in the free run.

    • cites [29] Scheibel, T., Weikl, T. & Buchner, J. Two chaperone sites in Hsp90 differing in substrate specificity and ATP dependence. Proc. Natl Acad. Sci. USA 95, 1495–1499 (1998). source

      Not checked in the free run.

  • Premisecitation

    The fungal Hsp90 interactome displays a high degree of plasticity that depends on environmental conditions.

    “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.”
    • Also stated in: § Plasticity of the Hsp90 interactome · boosted
      “Clearly the Hsp90 interactome displays substantial environmental contingency67.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Diezmann, S., Michaut, M., Shapiro, R. S., Bader, G. D. & Cowen, L. E. Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry. PLoS Genet. 8, e1002562 (2012). The first description of the Hsp90 interactome and its plasticity in a fungal pathogen. source

      Not checked in the free run.

    • cites [92] McClellan, A. J. et al. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121–135 (2007). This work reveals the plasticity of the S. cerevisiae Hsp90 interactome in response to stress. source

      Not checked in the free run.

  • Premisecitation

    Hsp90 is essential for the growth and viability of evolutionarily divergent yeasts such as S. cerevisiae, S. pombe and C. albicans even under normal growth conditions.

    “Indeed, Hsp90 is essential for the growth and viability of evolutionarily divergent yeasts such as S. cerevisiae, Schizosaccharomyces pombe and Candida albicans even under normal growth conditions14-16.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. & Lindquist, S. Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Mol. Cell. Biol. 9, 3919–3930 (1989). source

      Not checked in the free run.

    • cites [15] Swoboda, R. K. et al. Structure and regulation of the HSP90 gene from the pathogenic fungus Candida albicans. Infect. Immun. 63, 4506–4514 (1995). source

      Not checked in the free run.

    • cites [16] Kim, D.-U. et al. Analysis of a genome-wide set of gene deletions in the fission yeast Schizosaccharomyces pombe. Nature Biotech. 28, 617–623 (2010). source

      Not checked in the free run.

  • Premisecitation

    The fungal Hsp90 interactome includes numerous client proteins such as receptors, protein kinases and transcription factors.

    “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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [67] Diezmann, S., Michaut, M., Shapiro, R. S., Bader, G. D. & Cowen, L. E. Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry. PLoS Genet. 8, e1002562 (2012). The first description of the Hsp90 interactome and its plasticity in a fungal pathogen. source

      Not checked in the free run.

    • cites [78] Zhao, R. et al. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the Hsp90 chaperone. Cell 120, 715–727 (2005). This work maps the physical and genetic interactions of Hsp90 in S. cerevisiae. source

      Not checked in the free run.

    • cites [91] Millson, S. H. et al. A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p). Eukaryot. Cell 4, 849–860 (2005). The finding that the interaction of Hsp90 with a fungal MAPK client is influenced by environmental conditions. source

      Not checked in the free run.

    • cites [92] McClellan, A. J. et al. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121–135 (2007). This work reveals the plasticity of the S. cerevisiae Hsp90 interactome in response to stress. source

      Not checked in the free run.

    • cites [93] Wu, Z., Moghaddas Gholami, A. & Kuster, B. Systematic identification of the HSP90 candidate regulated proteome. Mol. Cell. Proteomics 11, M111.016675 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 6
  • May combine two claims. 13

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Hsp90 has crucial roles in protein folding and modulates the activities of key regulators.

    “Hsp90 is an essential, abundant, and ubiquitous eukaryotic chaperone that has crucial roles in protein folding and modulates the activities of key regulators.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Rev. Mol. Cell Biol. 11, 515–528 (2010). An excellent review of the structural dynamics of Hsp90 and the regulation of this chaperone. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hsp90 activity is tightly controlled via post-translational regulation and an autoregulatory loop involving Hsf1.

    “Furthermore, although Hsp90 levels increase following environmental challenges, Hsp90 activity is tightly controlled via post-translational regulation and an autoregulatory loop involving the heat shock transcription factor, Hsf1.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Leach, M. D., Tyc, K. M., Brown, A. J. P. & Klipp, E. Modelling the regulation of thermal adaptation in Candida albicans, a major fungal pathogen of humans. PLoS ONE 7, e32467 (2012). source

      Not checked in the free run.

    • cites [59] Duina, A. A., Kalton, H. M. & Gaber, R. F. Requirement for Hsp90 and a CyP-40-type cyclophilin in negative regulation of the heat shock response. J. Biol. Chem. 273, 18974–18978 (1998). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hsp90 has acted as an evolutionary capacitor during eukaryotic evolution.

    “Hence Hsp90 has acted as an evolutionary capacitor during eukaryotic evolution19-21.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). The description of Hsp90 as a capacitor of evolutionary change in eukaryotes. source

      Not checked in the free run.

    • cites [20] Cowen, L. E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005). A summary of the role of Hsp90 in the evolution of antifungal drug resistance. source

      Not checked in the free run.

    • cites [21] Chen, G., Bradford, W. D., Seidel, C. W. & Li, R. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482, 246–250 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Hsp90 protein has three domains and operates as a dimer.

    “Briefly, the Hsp90 protein has three domains and operates as a dimer24-26 (Figure 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Pearl, L. H. & Prodromou, C. Structure and in vivo function of Hsp90. Curr. Opin. Struct. Biol. 10, 46–51 (2000). source

      Not checked in the free run.

    • cites [25] Ali, M. M. et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006). The structural characterization of an Hsp90–co-chaperone complex. source

      Not checked in the free run.

    • cites [26] Pearl, L. H., Prodromou, C. & Workman, P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem. J. 410, 439–453 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hsp90 is thought to generate "protein-folding reservoirs" that can buffer the phenotypic impact of mutations in client proteins, thereby facilitating evolutionary change.

    “As a direct consequence of its role in maintaining the structural integrity of its client proteins, Hsp90 is thought to generate “protein-folding reservoirs” that can buffer the phenotypic impact of mutations in client proteins, thereby facilitating evolutionary change18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Jarosz, D. F. & Lindquist, S. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330, 1820–1824 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hsp90 has weak intrinsic ATPase activity that is modulated by interactions with client proteins and co-chaperones.

    “Hsp90 has weak intrinsic ATPase activity that is modulated by interactions with client proteins and co-chaperones.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [17] Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Rev. Mol. Cell Biol. 11, 515–528 (2010). An excellent review of the structural dynamics of Hsp90 and the regulation of this chaperone. source

      Not checked in the free run.

    • cites [23] Li, J., Soroka, J. & Buchner, J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim. Biophys. Acta 1823, 624–635 (2012). An outstanding review on the Hsp90 chaperone cycle and Hsp90 co-chaperones. source

      Not checked in the free run.

    • cites [24] Pearl, L. H. & Prodromou, C. Structure and in vivo function of Hsp90. Curr. Opin. Struct. Biol. 10, 46–51 (2000). source

      Not checked in the free run.

    • cites [25] Ali, M. M. et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006). The structural characterization of an Hsp90–co-chaperone complex. source

      Not checked in the free run.

    • cites [26] Pearl, L. H., Prodromou, C. & Workman, P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem. J. 410, 439–453 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hsp90 is naturally abundant in fungal cells and is induced to even greater levels by heat shock and other proteotoxic stresses.

    “Hsp90 is naturally abundant in fungal cells and is induced to even greater levels by heat shock and other proteotoxic stresses10,15,32-35.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [10] Nicholls, S., Leach, M. D., Priest, C. L. & Brown, A. J. Role of the heat shock transcription factor, Hsf1, in a major fungal pathogen that is obligately associated with warm-blooded animals. Mol. Microbiol. 74, 844–861 (2009). source

      Not checked in the free run.

    • cites [15] Swoboda, R. K. et al. Structure and regulation of the HSP90 gene from the pathogenic fungus Candida albicans. Infect. Immun. 63, 4506–4514 (1995). source

      Not checked in the free run.

    • cites [32] Chen, D. et al. Global transcriptional responses of fission yeast to environmental stress. Mol. Biol. Cell 14, 214–229 (2003). source

      Not checked in the free run.

    • cites [33] Steen, B. R. et al. Cryptococcus neoformans gene expression during experimental cryptococcal meningitis. Eukaryot. Cell 2, 1336–1349 (2003). source

      Not checked in the free run.

    • cites [34] Albrecht, D., Guthke, R., Brakhage, A. A. & Kniemeyer, O. Integrative analysis of the heat shock response in Aspergillus fumigatus. BMC Genomics 11, 32 (2010). source

      Not checked in the free run.

    • cites [35] Minchiotti, G., Gargano, S. & Maresca, B. The intron-containing hsp82 gene of the dimorphic pathogenic fungus Histoplasma capsulatum is properly spliced in severe heat shock conditions. Mol. Cell. Biol. 11, 5624–5630 (1991). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Hsp90 is an essential component of the cytoplasmic Hsp90-Hsp70 chaperone network that promotes protein folding and refolding in eukaryotic cells.

    “Hsp90 is an essential component of the cytoplasmic Hsp90-Hsp70 chaperone network that promotes protein folding and refolding in eukaryotic cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Rev. Mol. Cell Biol. 11, 515–528 (2010). An excellent review of the structural dynamics of Hsp90 and the regulation of this chaperone. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hsp90 is an essential, abundant, and ubiquitous eukaryotic chaperone.

    “Hsp90 is an essential, abundant, and ubiquitous eukaryotic chaperone that has crucial roles in protein folding and modulates the activities of key regulators.”
    • Also stated in: § Introduction · plain
      “Indeed, Hsp90 is essential for the growth and viability of evolutionarily divergent yeasts such as S. cerevisiae, Schizosaccharomyces pombe and Candida albicans even under normal growth conditions14-16.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. & Lindquist, S. Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Mol. Cell. Biol. 9, 3919–3930 (1989). source

      Not checked in the free run.

    • cites [15] Swoboda, R. K. et al. Structure and regulation of the HSP90 gene from the pathogenic fungus Candida albicans. Infect. Immun. 63, 4506–4514 (1995). source

      Not checked in the free run.

    • cites [16] Kim, D.-U. et al. Analysis of a genome-wide set of gene deletions in the fission yeast Schizosaccharomyces pombe. Nature Biotech. 28, 617–623 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The Hsp90 transistor probably modulates fungal signalling networks in response to other proteotoxic stresses that influence Hsp90 availability.

    “Furthermore, the Hsp90 transistor probably modulates fungal signalling networks in response to other proteotoxic stresses that influence Hsp90 availability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cell integrity and Ca++-calmodulin pathways play major parts in antifungal drug tolerance.

    “These pathways play major parts in antifungal drug tolerance”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] Singh, S. D. et al. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 5, e1000532 (2009). source

      Not checked in the free run.

    • cites [101] LaFayette, S. L. et al. PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog. 6, e1001069 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Hsp90 has a central role in tuning cellular outputs to thermal inputs, discussed primarily in the context of yeast species.

    “In conclusion, Hsp90 has a central role in tuning cellular outputs to thermal inputs, discussed here primarily in the context of yeast species.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hsf1 is essential for viability in yeasts, and is required for the basal expression of HSP genes.

    “Hsf1 is essential for viability in yeasts10,38,39, and is required for the basal expression of HSP genes10,39,40.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Nicholls, S., Leach, M. D., Priest, C. L. & Brown, A. J. Role of the heat shock transcription factor, Hsf1, in a major fungal pathogen that is obligately associated with warm-blooded animals. Mol. Microbiol. 74, 844–861 (2009). source

      Not checked in the free run.

    • cites [38] Wiederrecht, G., Seto, D. & Parker, C. S. Isolation of the gene encoding the S. cerevisiae heat shock transcription factor. Cell 54, 841–853 (1988). source

      Not checked in the free run.

    • cites [39] Sorger, P. K. & Pelham, H. R. B. Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation. Cell 54, 855–864 (1988). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulation of a stress response either by heat shock or increased expression of HSF-1 reduces the phenotypic effects of mutations in C. elegans.

    “Furthermore, the link between Hsp90, Hsf1 and environmental stress has been reinforced by the recent observation that stimulation of a stress response either by heat shock or increased expression of HSF-1 reduces the phenotypic effects of mutations in the nematode Caenorhabditis elegans137.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Casanueva, M. O., Burga, A. & Lehner, B. Fitness trade-offs and environmentally induced mutation buffering in isogenic C. elegans. Science 335, 82–85 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hsp90 can enable the phenotypic effects of new mutations either by stabilizing mutant regulators or by stabilizing non-mutant regulators that mediate signalling required for adaptation.

    “Second, Hsp90 can enable the phenotypic effects of new mutations either by stabilizing mutant regulators or by stabilizing non-mutant regulators that mediate signalling required for adaptation.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [20] Cowen, L. E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005). A summary of the role of Hsp90 in the evolution of antifungal drug resistance. source

      Not checked in the free run.

    • cites [88] Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761–772 (2005). source

      Not checked in the free run.

    • cites [135] Cowen, L. E. The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nature Rev. Microbiol. 6, 187–198 (2008). source

      Not checked in the free run.

    • cites [136] Xu, Y. & Lindquist, S. Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Natl Acad. Sci. USA 90, 7074–7078 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hsp90 influences approximately 20% of natural genetic variation in S. cerevisiae, serving both to maintain phenotypic robustness and promote diversification.

    “A recent study exploiting the genetic tractability of S. cerevisiae, revealed that Hsp90 influences approximately 20% of natural genetic variation serving both to maintain phenotypic robustness and promote diversification18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Jarosz, D. F. & Lindquist, S. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330, 1820–1824 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Hsp90 has a multitude of impacts on cellular circuitry: as a capacitor that buffers genetic variation until released by stress; as a potentiator that enables the phenotypic effects of new mutations; and as a transistor that tunes cellular outputs to environmental inputs.

    “Thus, Hsp90 has a multitude of impacts on cellular circuitry: as a capacitor that buffers genetic variation until released by stress; as a potentiator that enables the phenotypic effects of new mutations; and as a transistor that tunes cellular outputs to environmental inputs.”
    Quote in the paperNot a substantial claim
17 of 17

  • The authors state this as an assumption.

    Hsp90 displays differing affinities for different client proteins.

    “However, for the purpose of this discussion, let us simplify things by considering merely that Hsp90 displays differing affinities for different client proteins.”
    “Let us then, for the sake of discussion, make the likely presumptions that Hsp90 displays differing affinities for different client proteins, and that changes in ambient temperature affect the affinity of Hsp90 for some client proteins more than others.”

  • The authors state this as an assumption.

    Changes in ambient temperature affect the affinity of Hsp90 for some client proteins more than others.

    “Let us then, for the sake of discussion, make the likely presumptions that Hsp90 displays differing affinities for different client proteins, and that changes in ambient temperature affect the affinity of Hsp90 for some client proteins more than others.”

  • The paper relies on this without support.

    Cells are constantly tuning Hsp90 levels to subtle changes in ambient temperature.

    “Mathematical modelling has strongly suggested that cells are constantly tuning Hsp90 levels to subtle changes in ambient temperature.”

  • The paper relies on this without support.

    Hsp90 is one of the most ancient and highly conserved regulators of cellular signalling.

    “as Hsp90 is one of the most ancient and highly conserved regulators of cellular signalling”
4 of 4

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Authors
Leach, M. D., Klipp, E., Cowen, L. E., & Brown, A. J. P.
Affiliations
  • University of Toronto (CA)
  • Humboldt-Universität zu Berlin (DE)
  • University of Aberdeen (GB)
Corresponding author
Brown, Alistair J. P.
ORCID
Venue
Nature Reviews Microbiology
Publisher
Springer Science and Business Media LLC
Published
2012-09-14
Volume
10
Issue
10
Pages
693-704
ISSN
  • 1740-1526 (ISSN-L)
  • 1740-1534
DOI
10.1038/nrmicro2875
PMC
PMC3660702
OpenAlex
W2068328991
Cited by
107
References
145
Citations by year
2026: 4 · 2025: 5 · 2024: 2 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 10 · 2019: 5 · 2018: 8 · 2017: 11 · 2016: 13 · 2015: 10 · 2014: 9 · 2013: 6 · 2012: 2
FWCI
0.79
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Microbiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (097377/Z/11/Z, 097377, 096072, 080088)
  • European Commission
  • Canadian Institutes of Health Research (119520_1, MOP-86452)
  • Biotechnology and Biological Sciences Research Council (BB/D009308/1, BB/F00513X/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
HSP90, Hsp90 client proteins, HSF1, post-translational regulation, protein folding, molecular chaperones, environmental stress response, protein kinases, transcription factors
MeSH terms
Fungal Proteins, Fungi, Signal Transduction, Gene Expression Regulation, Fungal, HSP90 Heat-Shock Proteins, Feedback, Physiological, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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