VPS18

PF3D7_1309700 (VPS18) is a core subunit of the P. falciparum Vps-C/HOPS-CORVET vesicle tethering complex that supports membrane fusion events across the intraerythrocytic cycle (PMID:40198740, PMID:40626728). Co-immunoprecipitation and mass spectrometry of PfVps16 co-purified all four canonical Vps-C core components (VPS11, VPS16, VPS18, VPS33), confirming VPS18 membership in this complex (PMID:40626728). Functionally, early conditional depletion of VPS18 (with other core subunits) arrests parasite development and causes endosomes to accumulate without fusing to the digestive vacuole membrane, implicating VPS18 in endocytosis and host cell cytosol uptake during trophozoite stages (PMID:40198740). Late depletion instead disrupts merozoite invasion by mistargeting proteins destined for the rhoptries and micronemes, producing reduced rhoptry volume and vesicle accumulation in schizonts, indicating a stage-specific role in post-Golgi organelle biogenesis (PMID:40198740). VPS18 phosphorylation increases upon knockdown of the phosphatase PfPP1, placing it among potential (direct or indirect) PfPP1 substrates (PMID:32669539). Beyond its complex membership and these depletion phenotypes, no further mechanistic detail specific to VPS18 has been characterized in the available corpus.

1. 2013 Low

   Before any functional work, it was unknown whether Plasmodium retained a canonical vesicle-tethering machinery; comparative genomics established that VPS18 is one of four conserved Vps-C core components present in the P. falciparum genome, predicting a tethering role.

   Evidence Comparative genomic/bioinformatic analysis across twelve apicomplexan genomes

   PMID:24086721

   Open questions at the time

   • Computational prediction only, no direct experiment on VPS18
   • Does not demonstrate physical assembly of the complex
   • No cellular localization or function tested
2. 2020 Low

   The question of whether VPS18 activity is post-translationally regulated was partially addressed by a phosphoproteomic screen showing its phosphorylation rises when PfPP1 is depleted, nominating it as a phosphatase target.

   Evidence Phosphoproteomic analysis following PfPP1-DD conditional knockdown

   PMID:32669539

   Open questions at the time

   • VPS18 identified only among screen hits, no direct follow-up
   • Cannot distinguish direct vs indirect dephosphorylation by PfPP1
   • Functional consequence of the phosphosite unknown
3. 2025 Medium

   Whether the predicted Vps-C complex actually assembles in P. falciparum was answered by reciprocal Co-IP/MS of PfVps16, which co-purified VPS18 with the other three core members, confirming physical complex membership.

   Evidence Immunoprecipitation followed by mass spectrometry of PfVps16

   PMID:40626728

   Open questions at the time

   • Does not resolve whether VPS18 is shared between distinct HOPS vs CORVET assemblies
   • Stoichiometry and subunit contacts not defined
   • No structural model of the complex
4. 2025 Medium

   The cellular function of VPS18 was resolved by conditional depletion, which showed it is required at distinct life-cycle stages: early loss blocks endocytic fusion to the digestive vacuole, while late loss mistargets rhoptry/microneme proteins and impairs invasion.

   Evidence Conditional knockdown (knock-sideways/rapalog) with Giemsa, invasion assays, protein localization, and ultrastructure-expansion microscopy

   PMID:40198740

   Open questions at the time

   • Phenotypes reflect depletion of multiple core subunits together, not VPS18 alone
   • Molecular tethering mechanism and membrane targets not defined
   • Single lab, no reciprocal genetic complementation shown

• It remains unknown how VPS18 specifically contributes to Vps-C complex function distinct from its partner subunits, and whether its PfPP1-regulated phosphorylation controls its tethering activity.
• No VPS18-specific domain or interaction interface mapped
• Functional role of phosphorylation state untested
• Contribution to HOPS vs CORVET assemblies unresolved