Abstract
ABSTRACTMechanisms 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. P. falciparum ATG18 (PfATG18) and T. gondii ATG18 (TgATG18) interact with 3′-PIPs but exhibited differences in their specificity of interaction with the ligand PIP. The conditional knockdown of T. gondii or P. falciparum 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.
Highlights
Mechanisms by which 3=-phosphorylated phosphoinositides (3=-PIPs) regulate the development of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are poorly understood
We demonstrate that P. falciparum and T. gondii ATG18 (Pf/TgATG18) are involved in apicoplast biogenesis and depletion of ATG18 in P. falciparum and T. gondii resulted in “delayed death” phenotype, a phenomenon previously associated with the loss of the plastid [19]
TGGT1_220160 exhibited significant homology over almost the entire length of the protein (41%) as indicated by the ClustalW-based alignment, and structure-based comparison indicated that all seven blades of the ATG18 -propeller may be conserved in Plasmodium falciparum or Toxoplasma gondii ATG18 (Pf/TgATG18)
Summary
Mechanisms by which 3=-phosphorylated phosphoinositides (3=-PIPs) regulate the development of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are poorly understood. 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. 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. 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. We demonstrate that P. falciparum and T. gondii ATG18 (Pf/TgATG18) are involved in apicoplast biogenesis and depletion of ATG18 in P. falciparum and T. gondii resulted in “delayed death” phenotype, a phenomenon previously associated with the loss of the plastid [19]
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