International Centre for Genetic Engineering and Biotechnology, New Delhi 110 067, India.
ApicoLipid Team, Institute for Advanced Biosciences, CNRS UMR5309, Université Grenoble Alpes, INSERM U1209, Grenoble, France.
Cell Rep. 2023 Apr 25;42(4):112251. doi: 10.1016/j.celrep.2023.112251. Epub 2023 Apr 3.
Phospholipid metabolism is crucial for membrane biogenesis and homeostasis of Plasmodium falciparum. To generate such phospholipids, the parasite extensively scavenges, recycles, and reassembles host lipids. P. falciparum possesses an unusually large number of lysophospholipases, whose roles and importance remain to be elucidated. Here, we functionally characterize one P. falciparum lysophospholipase, PfLPL3, to reveal its key role in parasite propagation during asexual blood stages. PfLPL3 displays a dynamic localization throughout asexual stages, mainly localizing in the host-parasite interface. Inducible knockdown of PfLPL3 disrupts parasite development from trophozoites to schizont, inducing a drastic reduction in merozoite progenies. Detailed lipidomic analyses show that PfLPL3 generates fatty acids from scavenged host lipids to generate neutral lipids. These are then timely mobilized to allow schizogony and merozoite formation. We then identify inhibitors of PfLPL3 from Medicine for Malaria Venture (MMV) with potent antimalarial activity, which could also serve as pertinent chemical tools to study parasite lipid synthesis.
磷脂代谢对于疟原虫的膜生物发生和内环境稳定至关重要。为了产生这些磷脂，寄生虫广泛地搜刮、回收和重新组装宿主脂质。疟原虫拥有异常数量的溶血磷脂酶，但其作用和重要性仍有待阐明。在这里，我们对一种疟原虫溶血磷脂酶 PfLPL3 进行了功能表征，揭示了它在无性血阶段寄生虫繁殖中的关键作用。PfLPL3 在无性阶段表现出动态定位，主要定位于宿主-寄生虫界面。PfLPL3 的诱导性敲低会破坏从滋养体到裂殖体的寄生虫发育，导致裂殖子后代数量急剧减少。详细的脂质组学分析表明，PfLPL3 从搜刮的宿主脂质中产生脂肪酸，以生成中性脂质。然后这些脂质会被及时动员，以允许裂殖和裂殖子形成。随后，我们从疟疾药物发现基金会 (MMV) 中鉴定出 PfLPL3 的抑制剂，这些抑制剂具有很强的抗疟活性，也可以作为研究寄生虫脂质合成的相关化学工具。
