Autophagy protein Atg7 is essential and druggable for maintaining malaria parasite cellular homeostasis and organelle biogenesis

Abstract

AbstractPlasmodiumparasites have a complex life cycle that transitions between mosquito and mammalian hosts and undergoes 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 theP. bergheiautophagy-related E1-like enzyme Atg7 is expressed in the blood 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 exocytosis of micronemes, organelle biogenesis and the formation of merozoites during liver stage development. Furthermore, we identified the compounds from the Maybridge library with a high docking score againstPfAtg7. We show that these compounds inhibit apicoplast biogenesis and parasite development in both blood and liver stages. Overall, this study establishes the essential functions of autophagy inPlasmodiumblood and liver stages and highlights the potential of using Atg7 as a drug target against malaria.