Abstract
The highly conserved, ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. In human pathogenic fungi, which kill more than 1.6 million patients each year worldwide, Hsp90 governs cellular morphogenesis, drug resistance, and virulence. Yet, our understanding of the regulatory mechanisms governing fungal Hsp90 function remains sparse. Post-translational modifications are powerful components of nature’s toolbox to regulate protein abundance and function. Phosphorylation in particular is critical in many cellular signaling pathways and errant phosphorylation can have dire consequences for the cell. In the case of Hsp90, phosphorylation affects its stability and governs its interactions with co-chaperones and clients. Thereby modulating the cell’s ability to cope with environmental stress. Candida albicans, one of the leading human fungal pathogens, causes ~750,000 life-threatening invasive infections worldwide with unacceptably high mortality rates. Yet, it remains unknown if and how Hsp90 phosphorylation affects C. albicans virulence traits. Here, we show that phosphorylation of Hsp90 is critical for expression of virulence traits. We combined proteomics, molecular evolution analyses and structural modeling with molecular biology to characterize the role of Hsp90 phosphorylation in this non-model pathogen. We demonstrated that phosphorylation negatively affects key virulence traits, such as the thermal stress response, morphogenesis, and drug susceptibility. Our results provide the first record of a specific Hsp90 phosphorylation site acting as modulator of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitations as antifungal drug targets.
Highlights
Fungi kill as many patients as tuberculosis and about three times as many as malaria each year (Bongomin et al, 2017)
To map casein kinase 2 (CK2) phosphorylation sites in C. albicans heat shock protein 90 (Hsp90) in situ, the wild-type strain and four mutants, each lacking one CK2 subunit, were grown in rich media at 30°C upon which epitope tagged Hsp90 was purified and analyzed by mass spectrometry
Our data indicate that phosphorylation of Hsp90S530 blocks expression of virulence traits while any alteration of Hsp90T25 resulted in a loss-of-function phenotype
Summary
Fungi kill as many patients as tuberculosis and about three times as many as malaria each year (Bongomin et al, 2017). One of the most deadly fungal pathogens, Candida albicans causes ~750,000 cases of invasive life-threatening bloodstream infections in immunocompromised patients worldwide each year (Bongomin et al, 2017), with mortality rates approaching 75% (Brown et al, 2012). The United States alone spent $4.5 billion on 75,055 hospitalizations necessitated by fungal disease over ten years (Benedict et al, 2018) while English NHS trusts spend annually approximately £90 million on antifungal drugs (Whitney et al, 2018). This already dire situation is further exacerbated by the ever-growing number of patients at risk of contracting invasive fungal infections. It is imperative to understand the biological principles underpinning fungal virulence to identify points of fragility suitable for therapeutic targeting
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
