Ergosterol distribution controls surface structure formation and fungal pathogenicity.
Ergosterol distribution controls surface structure formation and fungal pathogenicity.
复制标题
麦角甾醇的分布控制表面结构的形成和真菌致病性。
DOI：
10.1101/2023.02.17.528979
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Doering,TamaraL
中科院分区：
文献类型：
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作者：
Choy,HauLam;Gaylord,ElizabethA;Doering,TamaraL
麦角甾醇是真菌细胞膜中的主要甾醇，对确定膜流动性和调节细胞过程至关重要。虽然麦角固醇的合成已经在模式酵母中得到了很好的定义，但在真菌发病机制的背景下对固醇组织知之甚少。我们确定了一个逆行甾醇转运蛋白，Ysp2，在机会致病真菌新生隐球菌。我们发现，在模拟宿主的条件下缺乏Ysp2导致麦角固醇在质膜上的异常积累、质膜的内陷和细胞壁的畸形，这可以通过用抗真菌药物氟康唑抑制麦角固醇合成来功能性地拯救。我们还观察到，缺乏Ysp2的细胞错误定位细胞表面蛋白Pma1，并具有异常薄和可渗透的胶囊。由于麦角固醇分布的紊乱及其后果，ysp 2 β细胞不能在生理相关环境中存活，如宿主吞噬细胞，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发病机制中的重要性。重要提示新生隐球菌是一种机会性真菌病原体，每年在全球范围内导致超过10万人死亡。只有三种药物可用于治疗隐球菌病，并且这些药物受到毒性、可用性、成本和耐药性的不同限制。麦角甾醇是真菌中含量最丰富的甾醇，是调节细胞膜行为的关键成分。两种用于隐球菌感染的药物，阿替霉素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发病机制的多个方面的关键作用。这些研究证明了麦角固醇稳态在C中的作用。neoformansvirtuality，加深我们对已证实具有治疗重要性的途径的理解，并开辟一个新的研究领域。
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 pathogenCryptococcus 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.IMPORTANCECryptococcus neoformansis 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 inC. neoformansvirulence, deepen our understanding of a pathway with proven therapeutic importance, and open a new area of study.