ATG18

PF3D7_1012900 (ATG18) is a PROPPIN-family phosphoinositide-binding protein of Plasmodium falciparum that couples PI3P recognition to two distinct membrane compartments, functioning in both apicoplast inheritance and food-vacuole–associated autophagy-like processes (PMID:29089429, PMID:33843972). It binds 3'-phosphorylated phosphoinositides, including PI3P, through conserved PROPPIN PI3P-binding motifs, and this interaction is essential: conditional knockdown causes loss of the apicoplast, impaired replication, and a delayed-death phenotype, and ATG18 directs the membrane association and apicoplast localization of ATG8 (PMID:29089429). In asexual blood stages, ATG18 localizes to the food vacuole via dual determinants — PI3P binding (motif mutants fail to bind PI3P and mislocalize) and direct interaction with the food-vacuole MDR1 protein, which co-immunoprecipitates with ATG18 (PMID:33843972) — and it becomes enriched at the interfaces of multilobed food vacuoles during fission/fusion, with delivery occurring through the haemoglobin trafficking pathway (PMID:31863491). ATG18 expression is induced by starvation, marking participation in an autophagy-like survival response distinct from its apicoplast role (PMID:31863491), and its transcript levels are tightly coupled to proliferation, since both up- and downregulation retard growth (PMID:35510853). ATG18 co-localizes with Kelch13 and PI3P on haemoglobin-trafficking vesicles, and the T38I polymorphism confers a growth advantage under nutrient limitation, linking the protein to artemisinin-resistance–associated endocytic biology (PMID:30367653, PMID:35420484).

1. 2017 High

   Established that PF3D7_1012900 is a phosphoinositide-binding protein essential for apicoplast inheritance, defining its first molecular activity and an organellar role independent of any bulk-autophagy assumption.

   Evidence Conditional knockdown with apicoplast-loss phenotype, PIP-binding assays, and ATG8 localization microscopy in P. falciparum and T. gondii

   PMID:29089429

   Open questions at the time

   • Mechanism by which ATG18 directs ATG8 membrane association not resolved
   • Structural basis of PI3P recognition not determined
   • Whether apicoplast role requires MDR1 or other partners unknown
2. 2018 High

   Linked a natural ATG18 polymorphism (T38I) to a fitness advantage under nutrient limitation, connecting the protein's PIP-binding, stress-responsive puncta behavior to parasite adaptation.

   Evidence CRISPR/Cas9 introduction of T38I into k13-edited Dd2, nutrient-deprivation growth assays, PIP-binding assays, and drug library screening in P. falciparum

   PMID:30367653

   Open questions at the time

   • Molecular mechanism by which T38I improves nutrient-limited growth not defined
   • T38I did not alter susceptibility to antimalarials in a 72-h pulse, leaving its resistance relevance unclear
3. 2019 Medium

   Placed ATG18 at the food vacuole and in food-vacuole fission/fusion dynamics, and showed starvation-induced expression, establishing an autophagy-like blood-stage role separable from apicoplast biogenesis.

   Evidence Live fluorescence microscopy, starvation induction with RT-qPCR/western blot, and pharmacological perturbation of haemoglobin trafficking in P. falciparum

   PMID:31863491

   Open questions at the time

   • Trafficking route to the food vacuole inferred pharmacologically without reciprocal validation
   • Direct role in fission/fusion vs. passive enrichment not distinguished
4. 2021 High

   Defined the dual determinants of food-vacuole localization — PI3P binding via PROPPIN motifs plus direct interaction with MDR1 — providing a mechanistic anchor for ATG18 targeting.

   Evidence PI3P-binding mutant expression with localization readout, reciprocal co-immunoprecipitation of MDR1, and drug-treatment mislocalization in P. falciparum, with the interaction replicated for the P. berghei ortholog

   PMID:33843972

   Open questions at the time

   • Functional consequence of the MDR1 interaction for food-vacuole physiology not established
   • Whether MDR1 recruits ATG18 or vice versa unresolved
5. 2022 Medium

   Connected ATG18 to the haemoglobin-endocytosis and artemisinin-resistance machinery by demonstrating co-localization with Kelch13 and PI3P on trafficking vesicles and elevated expression in K13C580Y parasites.

   Evidence Co-localization microscopy and western-blot quantification across isogenic wild-type and K13C580Y strains with starvation induction in P. falciparum

   PMID:35420484

   Open questions at the time

   • Causal role of ATG18 in artemisinin resistance not demonstrated
   • Co-localization does not establish direct interaction with K13
6. 2022 Medium

   Confirmed ATG18 as an essential gene whose expression level is bidirectionally coupled to proliferation, showing both overexpression and repression impair growth.

   Evidence Inducible CRISPRi/a transcript modulation with RT-qPCR and asexual growth assays in P. falciparum

   PMID:35510853

   Open questions at the time

   • Single approach, single lab
   • Which downstream ATG18 function (apicoplast vs. food vacuole) drives the growth defect not dissected

• How ATG18 mechanistically bridges apicoplast inheritance and food-vacuole/haemoglobin-endocytosis pathways, and whether its association with resistance-linked Kelch13 vesicles is causal, remains unresolved.
• No structural model of the PROPPIN PI3P-binding interface
• Directionality and functional output of the ATG18–MDR1 and ATG18–K13 associations undefined
• Whether ATG18 drives membrane fission/fusion enzymatically or as a scaffold unknown