PT  - JOURNAL ARTICLE
AU  - Leenah Alaalm
AU  - Julia L. Crunden
AU  - Mark Butcher
AU  - Ulrike Obst
AU  - Ryann Whealy
AU  - Carolyn E. Williamson
AU  - Heath E. O’Brien
AU  - Christiane Schaffitzel
AU  - Gordon Ramage
AU  - Stephanie Diezmann
TI  - A novel Hsp90 phospho-switch modulates virulence in the major human fungal pathogen <em>Candida albicans</em>
AID  - 10.1101/2020.09.23.309831
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.23.309831
4099  - http://biorxiv.org/content/early/2020/11/11/2020.09.23.309831.short
4100  - http://biorxiv.org/content/early/2020/11/11/2020.09.23.309831.full
AB  - The ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. Hsp90 also regulates cellular morphogenesis, drug resistance, and virulence in human pathogenic fungi, which kill more than 1.6 million patients each year worldwide. Invasive fungal infections are difficult to treat due to the lack of effective antifungal therapies, resulting in mortality rates of up to 95%. As a key regulator of fungal virulence, Hsp90 is an attractive therapeutic target. However, fungal and animal homologs are highly conserved, impeding fungal-specific targeting. Thus, understanding the factors that regulate Hsp90 could provide an alternative strategy aimed at exclusively targeting this regulator of fungal virulence. Here, we demonstrate how CK2-mediated phosphorylation of two Hsp90 residues modulates virulence in a major fungal pathogen of humans, Candida albicans. We combined proteomics, molecular evolution and structural modelling with molecular biology to identify and characterize two Hsp90 phosphorylation sites. Phosphorylation negatively affects thermal stress response, morphogenesis, drug susceptibility and fungal virulence. Our results provide the first record of specific Hsp90 phosphorylation sites acting as modulators of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitation as antifungal drug targets.Competing Interest StatementThe authors have declared no competing interest.