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  • Review Article
  • Published:

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

Nature Reviews Microbiology volume 10, pages 693–704 (2012)Cite this article

Subjects

Key Points

  • Heat shock protein 90 (HSP90) is an essential, abundant and ubiquitous eukaryotic chaperone that plays crucial roles in the folding of its client proteins. Fungal Hsp90 has been shown to stabilize client proteins, buffering or potentiating the phenotypic impact of mutations and thereby acting as an evolutionary capacitor during fungal evolution.

  • In cellular timescales, fungal Hsp90 has been shown to interact with and modulate the activities of client proteins. These clients include key regulators such as protein kinases and transcription factors that control fungal growth, environmental adaptation and pathogenicity.

  • Fungal Hsp90 activity is tightly regulated and is induced in response to heat shock and other proteotoxic stresses. Hsp90 synthesis is controlled by an autoregulatory circuit involving heat shock transcription factor 1 (Hsf1), and Hsp90 binding specificity is modulated by post-transcriptional modification.

  • Straightforward mathematical modelling predicts that the degree to which Hsp90 binds specific client proteins depends on Hsp90 availability and the relative affinities of the Hsp90 chaperone for these client proteins. This prediction is consistent with the experimental observation that the fungal Hsp90 interactome displays considerable environmental plasticity.

  • This plasticity implies that environmental challenges promote transient changes in the profile of regulators bound by Hsp90 and, hence, modulate the activities of the corresponding signalling pathways. We propose that Hsp90 acts as a biological transistor that tunes the activity of fungal signalling networks to environmental conditions.

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.

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Figure 1: The Hsp90 chaperone cycle.
Figure 2: Hsp90 levels and activity are regulated at multiple levels.
Figure 3: The fungal Hsp90 chaperone machine and exemplar client proteins.
Figure 4: Alterations in Hsp90 concentrations are predicted to differentially affect interactions with specific client proteins.
Figure 5: The Hsp90 transistor could tune multiple cellular outputs in response to thermal input.

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Acknowledgements

The authors are grateful to numerous colleagues, and to J. Heitman in particular, for insightful discussions. M.D.L. is a Sir Henry Wellcome Postdoctoral Fellow (Wellcome Trust grant 096072). E.K. is supported by grants from the German Research Council (grants GRK 1772, SFB618 and SFB740), the German Ministry of Education and Research (grants 0315786A and 0315584B) and the European Commission (grants FINSysB, PITN-GA-2008-214004 and Unicellsys HEALTH-2007-201142). L.E.C. is supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund, a Canada Research Chair in Microbial Genomics and Infectious Disease, a Ministry of Research and Innovation (Ontario, Canada) Early Researcher Award, and by grants from the Natural Sciences and Engineering Research Council of Canada (Discovery Grant 355965) and the Canadian Institutes of Health Research (grants MOP-86452 and MOP-119520). A.J.P.B. is supported by grants from the UK Biotechnology and Biological Research Council (grants BB/D009308/1 and BB/F00513X/1), the Wellcome Trust (grants 080088 and 097377) and the European Commission (grants FINSysB, PITN-GA-2008-214004 and STRIFE ERC-2009-AdG-249793).

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Authors and Affiliations

  1. Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Michelle D. Leach & Leah E. Cowen

  2. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom

    Michelle D. Leach & Alistair J. P. Brown

  3. Theoretische Biophysik, Institut für Biologie, Mathematisch-Naturwissenschaftliche Fakultät I, Humboldt-Universität zu Berlin, Invalidenstraße 42, Berlin, 10115, Germany

    Edda Klipp

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Correspondence to Alistair J. P. Brown.

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Supplementary information

Supplementary informtation S1 (figure)

The fungal Hsp90 chaperone machine and its client proteins. (PDF 204 kb)

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Hsp90Int.DB

Glossary

Proteotoxic stresses

Cellular stress conditions that prompt the accumulation of unfolded or damaged proteins, or the formation of protein aggregates.

Heat shock elements

Consensus sequences that are present in the promoter regions of heat shock genes and are bound by heat shock transcription factor 1 (Hsf1), thereby activating the expression of these genes.

Hyperphosphorylation

The phosphorylation of a target protein at multiple residues.

S-nitrosylated

Containing a covalently attached nitrosyl group on the thiol moiety of one or more cysteine residues in a protein. These nitrosyl groups are added as a result of nitrosative stress.

Synthetic genetic phenotypes

Phenotypes that are not apparent as a result of a single perturbation alone, but are revealed by combining two mutations or genetic and pharmacological perturbations.

Chemical genomic screens

Screens that combine small-molecule inhibitors or activators with genome-wide mutant collections to identify mutations that confer sensitivity or resistance to these molecules.

Filamentation

The formation of cells with an elongated morphology, such as hyphae, pseudohyphae and yeast cells that have not undergone cell separation.

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Leach, M., Klipp, E., Cowen, L. et al. Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs. Nat Rev Microbiol 10, 693–704 (2012). https://doi.org/10.1038/nrmicro2875

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