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

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Abstract
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.

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