The glycerophosphocholine acyltransferase Gpc1 contributes to phosphatidylcholine biosynthesis, long-term viability, and embedded hyphal growth in Candida albicans.
The glycerophosphocholine acyltransferase Gpc1 contributes to phosphatidylcholine biosynthesis, long-term viability, and embedded hyphal growth in Candida albicans.
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DOI：
10.1016/j.jbc.2023.105543
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发表时间：
2024-01
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影响因子：
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通讯作者：
Patton-Vogt J
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作者：
King WR;Singer J;Warman M;Wilson D;Hube B;Lager I;Patton-Vogt J
白色念珠菌是一种寄生真菌，条件致病菌，是人类真菌感染的最常见原因。磷脂酰胆碱（PC），一种主要的真核甘油磷脂的生物合成，通过两个主要途径发生。在酿酒酵母和一些植物中，第三种PC合成途径，PC脱酰/再酰化途径（PC-DRP），已被表征。PC-DRP开始于脂质周转产物甘油磷酸胆碱（GPC）被GPC酰基转移酶Gpc 1酰化，形成Lyso-PC。然后，溶血PC被溶血脂质酰基转移酶Lpt 1酰化，以产生PC。重要的是，GPC（Gpc 1的底物）是宿主体内普遍存在的代谢物。GPC由白色念珠菌输入，并且主要GPC转运蛋白Git 3的缺失导致小鼠模型中的毒力降低。在这里，我们报告GPC可以直接酰化白色念珠菌的蛋白质产物orf19.988，ScGpc 1的同源物。通过脂质组学研究，我们发现Gpc 1的丢失导致PC水平的降低。这种降低发生在不存在外源性GPC的情况下，表明对PC水平的影响可能在GPC可用的人类宿主中更大。gpc 1 Δ/Δ菌株对靶向脂质代谢的抗真菌剂表现出几种敏感性。此外，Gpc 1的损失导致在包埋条件下的菌丝生长缺陷和长期细胞活力的降低。这些结果首次证明了Gpc 1和这种替代PC生物合成途径（PC-DRP）对病原真菌生理学的重要性。
Candida albicans is a commensal fungus, opportunistic pathogen, and the most common cause of fungal infection in humans. The biosynthesis of phosphatidylcholine (PC), a major eukaryotic glycerophospholipid, occurs through two primary pathways. In Saccharomyces cerevisiae and some plants, a third PC synthesis pathway, the PC deacylation/reacylation pathway (PC-DRP), has been characterized. PC-DRP begins with the acylation of the lipid turnover product, glycerophosphocholine (GPC), by the GPC acyltransferase, Gpc1, to form Lyso-PC. Lyso-PC is then acylated by lysolipid acyltransferase, Lpt1, to produce PC. Importantly, GPC, the substrate for Gpc1, is a ubiquitous metabolite available within the host. GPC is imported by C. albicans, and deletion of the major GPC transporter, Git3, leads to decreased virulence in a murine model. Here we report that GPC can be directly acylated in C. albicans by the protein product of orf19.988, a homolog of ScGpc1. Through lipidomic studies, we show loss of Gpc1 leads to a decrease in PC levels. This decrease occurs in the absence of exogenous GPC, indicating that the impact on PC levels may be greater in the human host where GPC is available. A gpc1Δ/Δ strain exhibits several sensitivities to antifungals that target lipid metabolism. Furthermore, loss of Gpc1 results in both a hyphal growth defect in embedded conditions and a decrease in long-term cell viability. These results demonstrate for the first time the importance of Gpc1 and this alternative PC biosynthesis route (PC-DRP) to the physiology of a pathogenic fungus.