{"gene":"PF3D7_1309700","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2025,"finding":"PF3D7_1309700 (VPS18) is a core subunit of the HOPS/CORVET tethering complex in P. falciparum and is required for parasite endocytosis and host cell cytosol uptake; early functional depletion of VPS18 (along with other core subunits) caused developmental arrest and accumulation of endosomes that failed to fuse to the digestive vacuole membrane.","method":"Conditional knockdown (knock-sideways/rapalog system) with phenotypic readout by Giemsa smear, cell size measurement, and nuclei counting; ultrastructure-expansion microscopy","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional depletion with defined cellular phenotype and ultrastructure imaging, single lab but multiple orthogonal readouts","pmids":["40198740"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PF3D7_1309700 (VPS18) is a core subunit of the HOPS/CORVET tethering complex in P. falciparum, and late depletion of the complex (including VPS18) caused severe defects in merozoite invasion due to mistargeting of proteins destined for rhoptries and micronemes, with ultrastructure-expansion microscopy revealing reduced rhoptry volume and vesicle accumulation in deficient schizonts.","method":"Conditional knockdown (knock-sideways/rapalog system) with invasion assay, protein localization imaging, and ultrastructure-expansion microscopy","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional depletion with defined invasion and organelle phenotype, ultrastructure imaging, single lab","pmids":["40198740"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PF3D7_1309700 (VPS18) is one of the four core Vps-C complex components (VPS11, VPS16, VPS18, VPS33) in P. falciparum, and immunoprecipitation/mass spectrometry of PfVps16 co-purified all four core members including VPS18, confirming VPS18 membership in the canonical Vps-C complex.","method":"Immunoprecipitation followed by mass spectrometry (Co-IP/MS) of PfVps16","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS identification, single lab, establishes complex membership","pmids":["40626728"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"VPS18 (PF3D7_1309700) phosphorylation increases >2-fold upon PfPP1 knockdown, identifying it as a potential substrate (directly or indirectly) of the phosphatase PfPP1 in P. falciparum.","method":"Phosphoproteomic analysis following PfPP1-DD conditional knockdown","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — VPS18 is listed among phosphopeptides in a phosphoproteomic screen but no direct mechanistic follow-up on VPS18 specifically was performed","pmids":["32669539"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"Bioinformatic/comparative genomic analysis identified VPS18 (PF3D7_1309700) as one of four conserved VpsC core components (VPS11, VPS16, VPS18, VPS33) of the HOPS/CORVET complexes retained in the P. falciparum genome, consistent with its role in vesicle tethering.","method":"Comparative genomic/bioinformatic analysis across twelve apicomplexan genomes","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational/bioinformatic identification only, no direct functional experiment on VPS18","pmids":["24086721"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1309700 (VPS18) is a core subunit of the P. falciparum HOPS/CORVET vesicle tethering complex—confirmed by co-immunoprecipitation/mass spectrometry—and is functionally required for endocytosis and digestive vacuole fusion during trophozoite stages, as well as for post-Golgi trafficking of proteins to the rhoptries and micronemes during schizogony, with its phosphorylation state additionally regulated by PfPP1."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2013,"claim":"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","pmids":["24086721"],"confidence":"Low","gaps":["Computational prediction only, no direct experiment on VPS18","Does not demonstrate physical assembly of the complex","No cellular localization or function tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"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","pmids":["32669539"],"confidence":"Low","gaps":["VPS18 identified only among screen hits, no direct follow-up","Cannot distinguish direct vs indirect dephosphorylation by PfPP1","Functional consequence of the phosphosite unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"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","pmids":["40626728"],"confidence":"Medium","gaps":["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"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"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","pmids":["40198740"],"confidence":"Medium","gaps":["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"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No VPS18-specific domain or interaction interface mapped","Functional role of phosphorylation state untested","Contribution to HOPS vs CORVET assemblies unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Vps-C core complex (VPS11, VPS16, VPS18, VPS33)","HOPS/CORVET tethering complex"],"partners":["PFVPS16","PFVPS11","PFVPS33","PFPP1 (PHOSPHOREGULATION)"],"other_free_text":["Early depletion causes developmental arrest and endosomes that fail to fuse with the digestive vacuole membrane [#0]","Late depletion reduces rhoptry volume and causes vesicle accumulation with mistargeting of rhoptry/microneme proteins, impairing invasion [#1]","Phosphorylation increases >2-fold upon PfPP1 knockdown, marking it a candidate PfPP1 substrate [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24086721","id":"PMC_24086721","title":"Comparative genomic analysis of multi-subunit tethering complexes demonstrates an ancient pan-eukaryotic complement and sculpting in Apicomplexa.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24086721","citation_count":54,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40626728","id":"PMC_40626728","title":"The Plasmodium falciparum homolog of Vps16 interacts with the core members of the Vps-C tethering complex.","date":"2025","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/40626728","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["VPS18"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40198740","id":"","title":"HOPS/CORVET tethering complexes are critical for endocytosis and protein trafficking to invasion related organelles in malaria parasites.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/40198740","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["VPS18"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32669539","id":"","title":"Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32669539","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["VPS18"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6665,"output_tokens":1434,"usd":0.020753,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6367,"output_tokens":2365,"usd":0.04548,"stage2_stop_reason":"end_turn"},"total_usd":0.066233,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"PF3D7_1309700 (VPS18) is a core subunit of the HOPS/CORVET tethering complex in P. falciparum and is required for parasite endocytosis and host cell cytosol uptake; early functional depletion of VPS18 (along with other core subunits) caused developmental arrest and accumulation of endosomes that failed to fuse to the digestive vacuole membrane.\",\n      \"method\": \"Conditional knockdown (knock-sideways/rapalog system) with phenotypic readout by Giemsa smear, cell size measurement, and nuclei counting; ultrastructure-expansion microscopy\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional depletion with defined cellular phenotype and ultrastructure imaging, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"40198740\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PF3D7_1309700 (VPS18) is a core subunit of the HOPS/CORVET tethering complex in P. falciparum, and late depletion of the complex (including VPS18) caused severe defects in merozoite invasion due to mistargeting of proteins destined for rhoptries and micronemes, with ultrastructure-expansion microscopy revealing reduced rhoptry volume and vesicle accumulation in deficient schizonts.\",\n      \"method\": \"Conditional knockdown (knock-sideways/rapalog system) with invasion assay, protein localization imaging, and ultrastructure-expansion microscopy\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional depletion with defined invasion and organelle phenotype, ultrastructure imaging, single lab\",\n      \"pmids\": [\"40198740\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PF3D7_1309700 (VPS18) is one of the four core Vps-C complex components (VPS11, VPS16, VPS18, VPS33) in P. falciparum, and immunoprecipitation/mass spectrometry of PfVps16 co-purified all four core members including VPS18, confirming VPS18 membership in the canonical Vps-C complex.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry (Co-IP/MS) of PfVps16\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS identification, single lab, establishes complex membership\",\n      \"pmids\": [\"40626728\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPS18 (PF3D7_1309700) phosphorylation increases >2-fold upon PfPP1 knockdown, identifying it as a potential substrate (directly or indirectly) of the phosphatase PfPP1 in P. falciparum.\",\n      \"method\": \"Phosphoproteomic analysis following PfPP1-DD conditional knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — VPS18 is listed among phosphopeptides in a phosphoproteomic screen but no direct mechanistic follow-up on VPS18 specifically was performed\",\n      \"pmids\": [\"32669539\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Bioinformatic/comparative genomic analysis identified VPS18 (PF3D7_1309700) as one of four conserved VpsC core components (VPS11, VPS16, VPS18, VPS33) of the HOPS/CORVET complexes retained in the P. falciparum genome, consistent with its role in vesicle tethering.\",\n      \"method\": \"Comparative genomic/bioinformatic analysis across twelve apicomplexan genomes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational/bioinformatic identification only, no direct functional experiment on VPS18\",\n      \"pmids\": [\"24086721\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1309700 (VPS18) is a core subunit of the P. falciparum HOPS/CORVET vesicle tethering complex—confirmed by co-immunoprecipitation/mass spectrometry—and is functionally required for endocytosis and digestive vacuole fusion during trophozoite stages, as well as for post-Golgi trafficking of proteins to the rhoptries and micronemes during schizogony, with its phosphorylation state additionally regulated by PfPP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2]. 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 [#2]. 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 [#0]. 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 [#1]. VPS18 phosphorylation increases upon knockdown of the phosphatase PfPP1, placing it among potential (direct or indirect) PfPP1 substrates [#3]. Beyond its complex membership and these depletion phenotypes, no further mechanistic detail specific to VPS18 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Comparative genomic/bioinformatic analysis across twelve apicomplexan genomes\",\n      \"pmids\": [\"24086721\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no direct experiment on VPS18\", \"Does not demonstrate physical assembly of the complex\", \"No cellular localization or function tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phosphoproteomic analysis following PfPP1-DD conditional knockdown\",\n      \"pmids\": [\"32669539\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"VPS18 identified only among screen hits, no direct follow-up\", \"Cannot distinguish direct vs indirect dephosphorylation by PfPP1\", \"Functional consequence of the phosphosite unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunoprecipitation followed by mass spectrometry of PfVps16\",\n      \"pmids\": [\"40626728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional knockdown (knock-sideways/rapalog) with Giemsa, invasion assays, protein localization, and ultrastructure-expansion microscopy\",\n      \"pmids\": [\"40198740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No VPS18-specific domain or interaction interface mapped\", \"Functional role of phosphorylation state untested\", \"Contribution to HOPS vs CORVET assemblies unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0035658\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006897\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016192\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0006623\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"Vps-C core complex (VPS11, VPS16, VPS18, VPS33)\",\n      \"HOPS/CORVET tethering complex\"\n    ],\n    \"partners\": [\n      \"PfVps16\",\n      \"PfVps11\",\n      \"PfVps33\",\n      \"PfPP1 (phosphoregulation)\"\n    ],\n    \"other_free_text\": [\n      \"Early depletion causes developmental arrest and endosomes that fail to fuse with the digestive vacuole membrane [#0]\",\n      \"Late depletion reduces rhoptry volume and causes vesicle accumulation with mistargeting of rhoptry/microneme proteins, impairing invasion [#1]\",\n      \"Phosphorylation increases >2-fold upon PfPP1 knockdown, marking it a candidate PfPP1 substrate [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1309700","name":null,"product":"vacuolar protein sorting-associated protein 18, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1408200","name":null,"product":"vacuolar protein sorting-associated protein 18, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1410100","name":null,"product":"vacuolar protein sorting-associated protein 18, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"VPS18","evaluation":null}