Mishra Akancha, Rajput Suryansh, Srivastava Pratik Narain, Shabeer Ali H, Mishra Satish
Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
mBio. 2025 Feb 5;16(2):e0273524. doi: 10.1128/mbio.02735-24. Epub 2024 Dec 23.
parasites have a complex life cycle that transitions between mosquito and mammalian hosts, and undergo continuous cellular remodeling to adapt to various drastic environments. Following hepatocyte invasion, the parasite discards superfluous organelles for intracellular replication, and the remnant organelles undergo extensive branching and mature into hepatic merozoites. Autophagy is a ubiquitous eukaryotic process that permits the recycling of intracellular components. Here, we show that the autophagy-related E1-like enzyme Atg7 is expressed in the blood, sporozoites, and liver stages, localized to the parasite cytosol, and is essential for the localization of Atg8 on the membrane and the development of parasite blood and liver forms. We found that depleting Atg7 abolishes Atg8 lipidation, exocytosis of micronemes, organelle biogenesis, and the formation of merozoites during liver-stage development. Overall, this study establishes the essential functions of Atg7 in blood and liver stages, and highlights its role in maintaining the parasite's cellular homeostasis and organelle biogenesis.IMPORTANCEThe malaria life cycle involves two hosts, mosquitoes and vertebrates. parasites undergo complex intracellular and extracellular stages during this transition. Here, we report that an autophagy-related E1-like enzyme Atg7 is required to conjugate Atg8 on the apicoplast membrane. Atg7 depletion in resulted in the loss of Atg8 lipidation and multiple defects like clearance of micronemes, organelle biogenesis, and maturation of hepatic schizonts during liver-stage development. The essentiality of Atg7 in blood and liver stages suggests it is a prospective target for developing autophagy-specific inhibitors. These results highlight the importance of autophagy in malaria parasite development.
疟原虫具有复杂的生命周期，在蚊子和哺乳动物宿主之间转换，并不断进行细胞重塑以适应各种极端环境。侵入肝细胞后，疟原虫会丢弃多余的细胞器进行细胞内复制，剩余的细胞器会进行广泛分支并成熟为肝内裂殖子。自噬是一种普遍存在的真核生物过程，可实现细胞内成分的循环利用。在此，我们表明自噬相关的E1样酶Atg7在血液、子孢子和肝脏阶段均有表达，定位于疟原虫细胞质中，对于Atg8在膜上的定位以及疟原虫血液和肝脏形态的发育至关重要。我们发现，敲除Atg7会消除Atg8脂化、微线体胞吐、细胞器生物发生以及肝脏阶段发育过程中裂殖子的形成。总体而言，本研究确立了Atg7在血液和肝脏阶段的重要功能，并突出了其在维持疟原虫细胞内稳态和细胞器生物发生中的作用。重要性疟疾的生命周期涉及两个宿主，即蚊子和脊椎动物。疟原虫在这种转换过程中经历复杂的细胞内和细胞外阶段。在此，我们报告一种自噬相关的E1样酶Atg7是Atg8结合到顶质体膜所必需的。敲除Atg7导致Atg8脂化丧失以及多种缺陷，如微线体清除、细胞器生物发生以及肝脏阶段发育过程中肝内裂殖体的成熟。Atg7在血液和肝脏阶段的必要性表明它是开发自噬特异性抑制剂的一个潜在靶点。这些结果突出了自噬在疟原虫发育中的重要性。
