Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans
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. Y...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2021.637836/full |
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| author | Leenah Alaalm Julia L. Crunden Julia L. Crunden Mark Butcher Ulrike Obst Ryann Whealy Carolyn E. Williamson Heath E. O’Brien Christiane Schaffitzel Gordon Ramage James Spencer Stephanie Diezmann Stephanie Diezmann |
| author_facet | Leenah Alaalm Julia L. Crunden Julia L. Crunden Mark Butcher Ulrike Obst Ryann Whealy Carolyn E. Williamson Heath E. O’Brien Christiane Schaffitzel Gordon Ramage James Spencer Stephanie Diezmann Stephanie Diezmann |
| author_sort | Leenah Alaalm |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T07:29:48Z |
| format | Article |
| id | doaj.art-ca17f57cc0c64ecf8c292a3a3f97e118 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-21T07:29:48Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-ca17f57cc0c64ecf8c292a3a3f97e1182022-12-21T19:11:35ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882021-08-011110.3389/fcimb.2021.637836637836Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicansLeenah Alaalm0Julia L. Crunden1Julia L. Crunden2Mark Butcher3Ulrike Obst4Ryann Whealy5Carolyn E. Williamson6Heath E. O’Brien7Christiane Schaffitzel8Gordon Ramage9James Spencer10Stephanie Diezmann11Stephanie Diezmann12Department of Biology & Biochemistry, University of Bath, Bath, United KingdomDepartment of Biology & Biochemistry, University of Bath, Bath, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomDepartment of Biology & Biochemistry, University of Bath, Bath, United KingdomMRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, United KingdomSchool of Biochemistry, University of Bristol, Bristol, United KingdomSchool of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomDepartment of Biology & Biochemistry, University of Bath, Bath, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomThe 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.https://www.frontiersin.org/articles/10.3389/fcimb.2021.637836/fullfungal virulencephospho-switchHsp90thermotolerancedrug responsemorphogenesis |
| spellingShingle | Leenah Alaalm Julia L. Crunden Julia L. Crunden Mark Butcher Ulrike Obst Ryann Whealy Carolyn E. Williamson Heath E. O’Brien Christiane Schaffitzel Gordon Ramage James Spencer Stephanie Diezmann Stephanie Diezmann Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans Frontiers in Cellular and Infection Microbiology fungal virulence phospho-switch Hsp90 thermotolerance drug response morphogenesis |
| title | Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans |
| title_full | Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans |
| title_fullStr | Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans |
| title_full_unstemmed | Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans |
| title_short | Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans |
| title_sort | identification and phenotypic characterization of hsp90 phosphorylation sites that modulate virulence traits in the major human fungal pathogen candida albicans |
| topic | fungal virulence phospho-switch Hsp90 thermotolerance drug response morphogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2021.637836/full |
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