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Review
. 2017 Oct;25(10):809-819.
doi: 10.1016/j.tim.2017.05.003. Epub 2017 May 23.

The Hsp90 Chaperone Network Modulates Candida Virulence Traits

Teresa R O'Meara  1 , Nicole Robbins  1 , Leah E Cowen  2
Affiliations
Review

The Hsp90 Chaperone Network Modulates Candida Virulence Traits

Teresa R O'Meara et al. Trends Microbiol. 2017 Oct.

Abstract

Hsp90 is a conserved molecular chaperone that facilitates the folding and function of client proteins. Hsp90 function is dynamically regulated by interactions with co-chaperones and by post-translational modifications. In the fungal pathogen Candida albicans, Hsp90 enables drug resistance and virulence by stabilizing diverse signal transducers. Here, we review studies that have unveiled regulators of Hsp90 function, as well as downstream effectors that govern the key virulence traits of morphogenesis and drug resistance. We highlight recent work mapping the Hsp90 genetic network in C. albicans under diverse environmental conditions, and how these interactions provide insight into circuitry important for drug resistance, morphogenesis, and virulence. Ultimately, elucidating the Hsp90 chaperone network will aid in the development of therapeutics to treat fungal disease.

Keywords: Candida albicans; Hsp90; development; drug resistance; stress response; virulence.

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Figures

Figure 1
Figure 1. Key Figure. Hsp90 genetic interactors play important roles in drug resistance and virulence
A recent Hsp90 chemical genetic network [39] was re-colored to emphasize the role of each interactor in drug resistance (blue), virulence (red), or both (purple). The network is composed of 158 genetic interactors identified in five different growth conditions (large grey boxes). T = tunicamycin, Flu = fluconazole, C = caspofungin. Each HSP90 genetic interactor is indicated by a rectangle, with edges connecting it to the environmental conditions in which it interacts with HSP90. Interactors with a thick black outline were identified as hypersensitive to Hsp90 inhibition in the absence of stress.
Figure 2
Figure 2. Models of Hsp90 regulation in C. albicans
Hsp90 has been found to be regulated at the transcriptional and post-translational levels in response to environmental signals, with Hsp90 functional capacity modulated by cellular stress. A. HSP90 transcription can be regulated by Hsf1 and Ahr1, in addition to other factors. B. Hsp90 can be post-translationally modified by phosphorylation and acetylation. The phosphorylated and deacetylated form is required for functions in client stabilization and drug resistance. The phosphatase and lysine acetyltransferases (KATs) involved have not been elucidated. C. Increased cellular stress can overwhelm the functional capacity of Hsp90, impairing its ability to chaperone specific client proteins. Unfolded proteins are represented by ‘cloud’ shapes.
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