Phosphatidylserine synthesis is essential for viability of the human fungal pathogen Cryptococcus neoformans
Phosphatidylserine synthesis is essential for viability of the human fungal pathogen Cryptococcus neoformans
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DOI：
10.1074/jbc.ra118.006738
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发表时间：
2019-02-15
影响因子：
4.8
通讯作者：
Xue, Chaoyang
中科院分区：
文献类型：
--
作者：
Konarzewska, Paulina;Wang, Yina;Xue, Chaoyang
磷脂是细胞膜结构的一个组成部分，可以通过新生生物合成途径或肯尼迪途径产生。对几种酵母的研究表明，磷脂酰丝氨酸（PS）是由cdp -二酰基甘油和丝氨酸合成的，这一途径与哺乳动物细胞中的合成途径不同，涉及到先前存在的磷脂的碱基交换反应。真菌特异性PS合成已被证明在真菌毒力中起重要作用，并已被提出作为一个有吸引力的药物靶点。然而，催化该反应的PS合成酶尚未在人类真菌病原体新型隐球菌中进行研究。本研究鉴定了该真菌的PS合成酶同源物（Cn Cho1）。cncho1在酿酒酵母CHO1 δ突变体中的异源表达挽救了该突变体在缺乏乙醇胺补充时的生长缺陷。此外，表达Cn cho1的Sc cho1 δ突变体具有PS合成酶活性，证实Cn cho1编码PS合成酶。我们还发现，新生c.n oformans的PS合成酶定位于内质网，对线粒体功能和细胞活力至关重要。值得注意的是，它的不足不能通过补充乙醇胺或胆碱来弥补，以通过肯尼迪途径合成磷脂酰乙醇胺（PE）或磷脂酰胆碱（PC）。这些发现提高了我们对病原真菌磷脂合成的认识，并表明PS合成酶可能是抗真菌药物的有用靶点。
Phospholipids are an integral part of the cellular membrane structure and can be produced by a de novo biosynthetic pathway and, alternatively, by the Kennedy pathway. Studies in several yeast species have shown that the phospholipid phosphatidylserine (PS) is synthesized from CDP-diacylglycerol and serine, a route that is different from its synthesis in mammalian cells, involving a base-exchange reaction from preexisting phospholipids. Fungal-specific PS synthesis has been shown to play an important role in fungal virulence and has been proposed as an attractive drug target. However, PS synthase, which catalyzes this reaction, has not been studied in the human fungal pathogen Cryptococcus neoformans. Here, we identified and characterized the PS synthase homolog (Cn Cho1) in this fungus. Heterologous expression of Cn CHO1 in a Saccharomyces cerevisiae cho1 Delta mutant rescued the mutant's growth defect in the absence of ethanolamine supplementation. Moreover, an Sc cho1 Delta mutant expressing Cn CHO1 had PS synthase activity, confirming that the Cn CHO1 encodes PS synthase. We also found that PS synthase in C. neoformans is localized to the endoplasmic reticulum and that it is essential for mitochondrial function and cell viability. Of note, its deficiency could not be complemented by ethanolamine or choline supplementation for the synthesis of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) via the Kennedy pathway. These findings improve our understanding of phospholipid synthesis in a pathogenic fungus and indicate that PS synthase may be a useful target for antifungal drugs.