Autophagy-Related Protein ATG18 Regulates Apicoplast Biogenesis in Apicomplexan Parasites

Mechanisms by which 3'-phosphorylated phosphoinositides (3'-PIPs) regulate the development of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are poorly understood. The catabolic process of autophagy, which is dependent on autophagy-related proteins (ATGs), is one of the major targets of 3'-PIPs in yeast and mammals. In the present study, we identified autophagy-related protein ATG18 as an effector of 3'-PIPs in these parasites. Pfalciparum ATG18 (PfATG18) and Tgondii ATG18 (TgATG18) interact with 3'-PIPs but exhibited differences in their specificity of interaction with the ligand PIP. The conditional knockdown of Tgondii or Pfalciparum ATG18 (Tg/PfATG18) impaired replication of parasites and resulted in their delayed death. Intriguingly, ATG18 depletion resulted in the loss of the apicomplexan parasite-specific nonphotosynthetic plastid-like organelle apicoplast, which harbors the machinery for biosynthesis of key metabolites, and the interaction of ATG18 to phosphatidylinositol 3-phosphate (PI3P) was critical for apicoplast inheritance. Furthermore, ATG18 regulates membrane association and apicoplast localization of ATG8. These findings provide insights into a novel noncanonical role of ATG18 in apicoplast inheritance. This function of ATG18 in organelle biogenesis is unprecedented in any organism and may be conserved across most apicomplexan parasites.IMPORTANCE Typically, autophagy is a catabolic process utilized by cells for their survival upon encountering nutrient-limiting conditions. The autophagy machinery is very tightly regulated, and autophagy-related genes (ATGs) play a pivotal role in this process. In the present study, we report a novel noncanonical function of autophagy-related protein ATG18 in inheritance of the nonphotosynthetic plastid-like organelle apicoplast in apicomplexan parasites Plasmodium and Toxoplasma ATG18 depletion in these parasites resulted in "delayed death," which was the result of loss of apicoplast and impaired parasite division. Pf/TgATG18 interact with 3'-phosphorylated PIPs, which guide their cellular localization in the parasite, which is essential for their function.