The causative agent of malaria, Plasmodium, replicates inside a membrane-bound parasitophorous vacuole (PV), which shields this intracellular parasite from the cytosol of the host cell ¹ . One common threat for intracellular pathogens is the homeostatic process of autophagy, through which cells capture unwanted intracellular material for lysosomal degradation ² . During the liver stage of a malaria infection, Plasmodium parasites are targeted by the autophagy machinery of the host cell, and the PV membrane (PVM) becomes decorated with several autophagy markers, including LC3 (microtubule-associated protein 1 light chain 3) ^3,4 . Here we show that Plasmodium berghei parasites infecting hepatic cells rely on the PVM transmembrane protein UIS3 to avoid elimination by host-cell-mediated autophagy. We found that UIS3 binds host LC3 through a non-canonical interaction with a specialized surface on LC3 where host proteins with essential functions during autophagy also bind. UIS3 acts as a bona fide autophagy inhibitor by competing with host LC3-interacting proteins for LC3 binding. Our work identifies UIS3, one of the most promising candidates for a genetically attenuated vaccine against malaria ⁵ , as a unique and potent mediator of autophagy evasion in Plasmodium. We propose that the protein-protein interaction between UIS3 and host LC3 represents a target for antimalarial drug development.

中文翻译：

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疟原虫 UIS3 螯合剂宿主 LC3 以避免被肝细胞中的自噬消除。

疟疾的病原体疟原虫在膜结合的寄生空泡 (PV) 内复制，该空泡将这种细胞内寄生虫与宿主细胞¹的胞质溶胶隔离开来。细胞内病原体的一个常见威胁是自噬的稳态过程，细胞通过该过程捕获不需要的细胞内物质以进行溶酶体降解²。在疟疾感染的肝脏阶段，疟原虫寄生虫被宿主细胞的自噬机制靶向，并且 PV 膜 (PVM) 被多种自噬标记物修饰，包括 LC3（微管相关蛋白 1 轻链 3）^{3， 4}. 在这里，我们显示感染肝细胞的伯氏疟原虫寄生虫依赖 PVM 跨膜蛋白 UIS3 来避免宿主细胞介导的自噬消除。我们发现 UIS3 通过与 LC3 上特定表面的非规范相互作用结合宿主 LC3，在自噬过程中具有基本功能的宿主蛋白也结合。UIS3 通过与宿主 LC3 相互作用蛋白竞争 LC3 结合来充当真正的自噬抑制剂。我们的工作确定 UIS3 是抗疟疾基因减毒疫苗的最有希望的候选者之一⁵，它是疟原虫逃避自噬的独特而有效的介质。我们提出 UIS3 和宿主 LC3 之间的蛋白质-蛋白质相互作用代表了抗疟药物开发的目标。