Ergosterol distribution controls surface structure formation and fungal pathogenicity
ABSTRACT Ergosterol, the major sterol in fungal membranes, is critical for defining membrane fluidity and regulating cellular processes. Although ergosterol synthesis has been well defined in model yeast, little is known about sterol organization in the context of fungal pathogenesis. We identified...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01353-23 |
| _version_ | 1797730233059639296 |
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| author | Hau Lam Choy Elizabeth A. Gaylord Tamara L. Doering |
| author_facet | Hau Lam Choy Elizabeth A. Gaylord Tamara L. Doering |
| author_sort | Hau Lam Choy |
| collection | DOAJ |
| description | ABSTRACT Ergosterol, the major sterol in fungal membranes, is critical for defining membrane fluidity and regulating cellular processes. Although ergosterol synthesis has been well defined in model yeast, little is known about sterol organization in the context of fungal pathogenesis. We identified a retrograde sterol transporter, Ysp2, in the opportunistic fungal pathogen Cryptococcus neoformans. We found that the lack of Ysp2 under host-mimicking conditions leads to abnormal accumulation of ergosterol at the plasma membrane, invagination of the plasma membrane, and malformation of the cell wall, which can be functionally rescued by inhibiting ergosterol synthesis with the antifungal drug fluconazole. We also observed that cells lacking Ysp2 mislocalize the cell surface protein Pma1 and have abnormally thin and permeable capsules. As a result of perturbed ergosterol distribution and its consequences, ysp2∆ cells cannot survive in physiologically relevant environments such as host phagocytes and are dramatically attenuated in virulence. These findings expand our knowledge of cryptococcal biology and underscore the importance of sterol homeostasis in fungal pathogenesis. IMPORTANCE Cryptococcus neoformans is an opportunistic fungal pathogen that kills over 100,000 people worldwide each year. Only three drugs are available to treat cryptococcosis, and these are variously limited by toxicity, availability, cost, and resistance. Ergosterol is the most abundant sterol in fungi and a key component in modulating membrane behavior. Two of the drugs used for cryptococcal infection, amphotericin B and fluconazole, target this lipid and its synthesis, highlighting its importance as a therapeutic target. We discovered a cryptococcal ergosterol transporter, Ysp2, and demonstrated its key roles in multiple aspects of cryptococcal biology and pathogenesis. These studies demonstrate the role of ergosterol homeostasis in C. neoformans virulence, deepen our understanding of a pathway with proven therapeutic importance, and open a new area of study. |
| first_indexed | 2024-03-12T11:41:16Z |
| format | Article |
| id | doaj.art-15ce59d610be448b9674d17b3f1ca4f8 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-12T11:41:16Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-15ce59d610be448b9674d17b3f1ca4f82023-08-31T15:04:21ZengAmerican Society for MicrobiologymBio2150-75112023-08-0114410.1128/mbio.01353-23Ergosterol distribution controls surface structure formation and fungal pathogenicityHau Lam Choy0Elizabeth A. Gaylord1Tamara L. Doering2Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USAABSTRACT Ergosterol, the major sterol in fungal membranes, is critical for defining membrane fluidity and regulating cellular processes. Although ergosterol synthesis has been well defined in model yeast, little is known about sterol organization in the context of fungal pathogenesis. We identified a retrograde sterol transporter, Ysp2, in the opportunistic fungal pathogen Cryptococcus neoformans. We found that the lack of Ysp2 under host-mimicking conditions leads to abnormal accumulation of ergosterol at the plasma membrane, invagination of the plasma membrane, and malformation of the cell wall, which can be functionally rescued by inhibiting ergosterol synthesis with the antifungal drug fluconazole. We also observed that cells lacking Ysp2 mislocalize the cell surface protein Pma1 and have abnormally thin and permeable capsules. As a result of perturbed ergosterol distribution and its consequences, ysp2∆ cells cannot survive in physiologically relevant environments such as host phagocytes and are dramatically attenuated in virulence. These findings expand our knowledge of cryptococcal biology and underscore the importance of sterol homeostasis in fungal pathogenesis. IMPORTANCE Cryptococcus neoformans is an opportunistic fungal pathogen that kills over 100,000 people worldwide each year. Only three drugs are available to treat cryptococcosis, and these are variously limited by toxicity, availability, cost, and resistance. Ergosterol is the most abundant sterol in fungi and a key component in modulating membrane behavior. Two of the drugs used for cryptococcal infection, amphotericin B and fluconazole, target this lipid and its synthesis, highlighting its importance as a therapeutic target. We discovered a cryptococcal ergosterol transporter, Ysp2, and demonstrated its key roles in multiple aspects of cryptococcal biology and pathogenesis. These studies demonstrate the role of ergosterol homeostasis in C. neoformans virulence, deepen our understanding of a pathway with proven therapeutic importance, and open a new area of study.https://journals.asm.org/doi/10.1128/mbio.01353-23Cryptococcus neoformansYsp2sterol transportergosterolvirulencemycology |
| spellingShingle | Hau Lam Choy Elizabeth A. Gaylord Tamara L. Doering Ergosterol distribution controls surface structure formation and fungal pathogenicity mBio Cryptococcus neoformans Ysp2 sterol transport ergosterol virulence mycology |
| title | Ergosterol distribution controls surface structure formation and fungal pathogenicity |
| title_full | Ergosterol distribution controls surface structure formation and fungal pathogenicity |
| title_fullStr | Ergosterol distribution controls surface structure formation and fungal pathogenicity |
| title_full_unstemmed | Ergosterol distribution controls surface structure formation and fungal pathogenicity |
| title_short | Ergosterol distribution controls surface structure formation and fungal pathogenicity |
| title_sort | ergosterol distribution controls surface structure formation and fungal pathogenicity |
| topic | Cryptococcus neoformans Ysp2 sterol transport ergosterol virulence mycology |
| url | https://journals.asm.org/doi/10.1128/mbio.01353-23 |
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