Choy Hau Lam, Gaylord Elizabeth A, Doering Tamara L
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
bioRxiv. 2023 Feb 17:2023.02.17.528979. doi: 10.1101/2023.02.17.528979.
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 . 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 thinner and more permeable capsules. As a result of perturbed ergosterol distribution and its consequences, Î" cells cannot survive in physiologically-rele-vant 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.
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 virulence, deepen our understanding of a pathway with proven therapeutic importance, and open a new area of study.
麦角固醇是真菌细胞膜中的主要固醇，对于确定膜流动性和调节细胞过程至关重要。尽管在模式酵母中麦角固醇的合成已得到充分阐明，但在真菌致病过程中固醇的组织情况却知之甚少。我们在机会性真菌病原体中鉴定出一种逆向固醇转运蛋白Ysp2。我们发现，在模拟宿主的条件下缺乏Ysp2会导致麦角固醇在质膜异常积累、质膜内陷以及细胞壁畸形，而用抗真菌药物氟康唑抑制麦角固醇合成可在功能上挽救这些现象。我们还观察到，缺乏Ysp2的细胞会使细胞表面蛋白Pma1定位错误，并且其荚膜更薄且通透性更高。由于麦角固醇分布紊乱及其后果，Δ细胞无法在诸如宿主吞噬细胞等生理相关环境中存活，并且毒力显著减弱。这些发现扩展了我们对隐球菌生物学的认识，并强调了固醇稳态在真菌致病过程中的重要性。
是一种机会性真菌病原体，每年在全球导致超过10万人死亡。治疗隐球菌病仅有三种药物可用，而这些药物在毒性、可获得性、成本和耐药性方面各有限制。麦角固醇是真菌中最丰富的固醇，也是调节膜行为的关键成分。用于隐球菌感染的两种药物两性霉素B和氟康唑靶向这种脂质及其合成，突出了其作为治疗靶点的重要性。我们发现了一种隐球菌麦角固醇转运蛋白Ysp2，并证明了其在隐球菌生物学和致病机制多个方面的关键作用。这些研究证明了麦角固醇稳态在毒力中的作用，加深了我们对一条已证实具有治疗重要性的途径的理解，并开辟了一个新的研究领域。
