{"gene":"PF3D7_1442600","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2008,"finding":"TREP (PF3D7_1442600) is a transmembrane protein with a short cytoplasmic tail typical of TRAP family members and a large extracellular region containing a single thrombospondin type 1 repeat (TSR) domain. Targeted disruption of the TREP gene in P. berghei sporozoites resulted in a highly diminished capacity to invade mosquito salivary glands and a severe defect in gliding motility, establishing that TREP is necessary for sporozoite gliding motility in the mosquito.","method":"Gene disruption (targeted gene knockout) in P. berghei; gliding motility assays; salivary gland invasion assays","journal":"International journal for parasitology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function genetic knockout with two distinct phenotypic readouts (gliding motility and salivary gland invasion) in a single focused study","pmids":["19000911"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"finding":"TREP (PF3D7_1442600) is expressed predominantly in oocyst-stage sporozoites (transcript level analysis by qRT-PCR), distinguishing its expression pattern from TRAP, which is expressed in salivary gland sporozoites.","method":"Quantitative reverse transcription PCR (qRT-PCR) of stage-specific transcripts","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (qRT-PCR), localization/expression without direct functional follow-up beyond the KO phenotype","pmids":["19000911"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"finding":"TREP (PF3D7_1442600/TLP) binds aldolase via its cytoplasmic tail, demonstrating that it couples to the actin-myosin motor machinery in the same manner as other TRAP family invasins. Genetic complementation showed the cytoplasmic tail of TREP can substitute for that of TRAP.","method":"Aldolase binding assay (in vitro pulldown); genetic complementation test in P. berghei","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assay combined with genetic complementation, two orthogonal methods in single study","pmids":["18441124"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"finding":"Targeted disruption of the TREP (PF3D7_1442600/TLP) gene in P. berghei resulted in decreased capacity for cell traversal by sporozoites and reduced infectivity in vivo, while in vitro sporozoite motility and hepatocyte invasion were unaffected, indicating a specific role for TREP in tissue traversal.","method":"Targeted gene disruption; in vivo infectivity assay; cell traversal assay; in vitro gliding motility and hepatocyte invasion assays","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple defined phenotypic readouts distinguishing traversal from motility and invasion","pmids":["18346224"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2010,"finding":"TREP (PF3D7_1442600/TLP) was found to play a specific role in sporozoite adhesion under static conditions; tlp− sporozoites moved 4 times less efficiently than wild-type sporozoites, as shown by total internal reflection fluorescence (TIRF) microscopy and flow-based adhesion assays. TREP acts in concert with TRAP and S6 to organize efficient adhesion prior to initiating motility.","method":"Total internal reflection fluorescence (TIRF) microscopy; sporozoite adhesion assays under flow and static conditions; tlp− mutant P. berghei sporozoites","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging with genetic mutants and two experimental conditions (static vs. flow), single lab","pmids":["20159960"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2011,"finding":"TREP (PF3D7_1442600/TLP)-deficient sporozoites show impaired adhesion resulting in altered migration patterns in complex environments. tlp− sporozoite speed and force generation are reduced, and the correlation between persistence length and dispersal breaks down, suggesting TREP contributes to environmental guidance of sporozoite migration.","method":"In vivo imaging in micro-fabricated obstacle arrays and skin; comparison of tlp− and wild-type sporozoite trajectories","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of KO parasites in defined environments, single lab, two experimental settings","pmids":["21698220"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2012,"finding":"TREP (PF3D7_1442600/TLP) knockout sporozoites are defective in cell traversal: they fail to traverse MDCK monolayers and are retained inside the MDCK cytoplasm, providing direct evidence for a role of TREP in cell traversal distinct from invasion.","method":"Cell traversal assay through MDCK monolayers; fluorescent dye retention assay; tlp KO P. berghei sporozoites","journal":"Journal of immunological methods","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO, single cell traversal assay with direct imaging evidence, single lab","pmids":["22306356"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"Protein O-fucosylation of TREP (PF3D7_1442600) by the Plasmodium protein O-fucosyltransferase POFUT2 is required for correct trafficking and stability of TREP (a TSR domain-bearing protein). POFUT2-deficient P. falciparum parasites show destabilization and incorrect trafficking of TSR-bearing proteins including TREP, with downstream defects in gliding motility, cell traversal, and hepatocyte invasion.","method":"Genetic disruption of POFUT2; protein stability/trafficking assays; life cycle phenotyping (gliding motility, cell traversal, hepatocyte invasion)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple orthogonal functional assays; TREP is one of several TSR proteins affected, so direct attribution to TREP specifically is partially inferred","pmids":["28916755"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"finding":"TREP (PF3D7_1442600/TLP)-deficient sporozoites generate lower traction forces on both dorsal and ventral surfaces compared to wild-type, as measured by laser tweezers and traction force microscopy. This demonstrates that TREP is an important element of the force-generating machinery during sporozoite gliding motility.","method":"Traction force microscopy; laser tweezers; tlp− mutant P. berghei sporozoites","journal":"Journal of microscopy","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — quantitative biophysical assays (traction force microscopy and optical tweezers) with genetic KO, single lab, single study","pmids":["40716091"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"finding":"Glycosylation of P. falciparum TRAP's TSR domain (O-fucosylation at Thr256 and C-mannosylation at Trp250) is critical for TRAP protein abundance and function. CRISPR/Cas9 glyco-null mutants (T256A and W250F) of PfTRAP showed dramatically reduced TRAP protein levels despite normal transcript levels, and were unable to productively colonize mosquito salivary glands and were severely impaired in gliding motility and hepatocyte invasion — phenotypes comparable to TRAP knockout. Note: this finding is for PfTRAP (TRAP, a different gene), not PF3D7_1442600/TREP.","method":"CRISPR/Cas9 site-directed mutagenesis; protein abundance analysis; life cycle fitness assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Excluded from TREP discoveries — this finding is about PfTRAP (a different gene), not PF3D7_1442600/TREP","pmids":["40667256"],"is_preprint":true,"attribution":[]}],"current_model":"TREP (PF3D7_1442600) is a sporozoite-expressed TRAP-family transmembrane protein with a TSR-containing extracellular domain and a short cytoplasmic tail that binds aldolase, coupling it to the parasite actin-myosin motor; in P. berghei, loss of TREP causes severe defects in gliding motility, salivary gland invasion, cell traversal, and traction force generation, while having no detectable effect on in vitro hepatocyte invasion, indicating that TREP functions specifically in the force-transduction and tissue-traversal steps of sporozoite transmission in the mosquito."},"narrative":{"mechanistic_narrative":"TREP (PF3D7_1442600) is a TRAP-family transmembrane protein of Plasmodium sporozoites that couples surface adhesion to the actin-myosin motor to drive gliding motility and tissue traversal during transmission in the mosquito [PMID:19000911, PMID:18441124]. It possesses a large extracellular region containing a single thrombospondin type 1 repeat (TSR) domain and a short cytoplasmic tail that binds aldolase, linking it to the glideosome; this tail is functionally interchangeable with that of TRAP [PMID:19000911, PMID:18441124]. In P. berghei, TREP is expressed predominantly in oocyst-stage sporozoites, distinguishing it from TRAP, which acts in salivary gland sporozoites, and its disruption severely impairs gliding motility, salivary gland invasion, cell traversal, and in vivo infectivity while leaving in vitro hepatocyte invasion intact — placing TREP specifically in the adhesion, force-transduction, and traversal steps rather than the final invasion step [PMID:19000911, PMID:18346224]. TREP contributes to substrate adhesion and to the traction forces sporozoites generate on both dorsal and ventral surfaces, so its loss reduces sporozoite speed, force generation, and environmental guidance during migration [PMID:20159960, PMID:21698220, PMID:40716091]. As a TSR-bearing protein, TREP requires O-fucosylation by the protein O-fucosyltransferase POFUT2 for correct trafficking and stability [PMID:28916755].","teleology":[{"year":2008,"claim":"It was unknown how TREP couples to the parasite invasion machinery; showing that its cytoplasmic tail binds aldolase and can substitute for the TRAP tail established that TREP links surface adhesion to the actin-myosin motor like other TRAP-family invasins.","evidence":"In vitro aldolase pulldown plus genetic complementation of TRAP by the TREP tail in P. berghei","pmids":["18441124"],"confidence":"High","gaps":["Does not identify the extracellular ligand engaged by the TSR domain","Does not resolve how tail-motor coupling is regulated during motility"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"claim":"The role of the traversal/adhesion step versus final invasion was unresolved; TREP disruption impaired cell traversal and in vivo infectivity but not in vitro hepatocyte invasion, isolating TREP function to tissue traversal rather than invasion.","evidence":"Targeted gene disruption with cell traversal, in vivo infectivity, and hepatocyte invasion assays in P. berghei","pmids":["18346224"],"confidence":"High","gaps":["Molecular basis of the traversal defect not defined","Does not explain why invasion is spared"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"claim":"TREP's stage of action and requirement for motility were unknown; knockout established it as necessary for gliding motility and salivary gland invasion, and qRT-PCR placed its expression in oocyst-stage sporozoites, distinguishing it from TRAP.","evidence":"Targeted knockout with gliding and salivary gland invasion assays plus stage-specific qRT-PCR in P. berghei (and P. falciparum expression)","pmids":["19000911"],"confidence":"High","gaps":["Transcript-level expression not corroborated at protein level in this study","Functional division of labor with TRAP not mechanistically dissected"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2010,"claim":"Whether TREP acts before or during motility was unclear; live imaging showed tlp- sporozoites adhere poorly under static conditions, establishing that TREP organizes efficient adhesion in concert with TRAP and S6 prior to motility initiation.","evidence":"TIRF microscopy and static/flow adhesion assays with tlp- P. berghei sporozoites","pmids":["20159960"],"confidence":"Medium","gaps":["Does not resolve the adhesive ligand or receptor engaged","Relative contributions of TREP, TRAP, and S6 not quantified"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2011,"claim":"It was unknown whether TREP influences directional migration in tissue; imaging in obstacle arrays and skin showed tlp- sporozoites have reduced speed and force and lose the persistence-dispersal correlation, indicating TREP contributes to environmental guidance of migration.","evidence":"In vivo imaging of tlp- versus wild-type sporozoite trajectories in micro-fabricated arrays and skin","pmids":["21698220"],"confidence":"Medium","gaps":["Mechanism linking adhesion to trajectory guidance not defined","Force reduction not directly measured biophysically here"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2012,"claim":"Direct evidence for TREP in traversal (versus mere motility loss) was needed; knockout sporozoites failed to traverse MDCK monolayers and were retained in the cytoplasm, confirming a traversal-specific role.","evidence":"MDCK monolayer traversal and dye-retention assays with tlp knockout P. berghei sporozoites","pmids":["22306356"],"confidence":"Medium","gaps":["Does not identify the molecular effector of cell exit","Single traversal system"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"claim":"How TREP achieves stability and surface trafficking was unknown; loss of POFUT2 destabilized and mistrafficked TSR-bearing proteins including TREP, establishing O-fucosylation as a post-translational requirement for TREP maturation.","evidence":"Genetic disruption of POFUT2 with protein stability/trafficking and life-cycle phenotyping in P. falciparum and P. berghei","pmids":["28916755"],"confidence":"Medium","gaps":["TREP is one of several affected TSR proteins, so TREP-specific effect is partly inferred","Fucosylation site on TREP not mapped in this study"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"claim":"Whether TREP contributes to physical force generation was untested; biophysical measurement showed tlp- sporozoites generate lower traction forces on both surfaces, placing TREP within the force-generating machinery of gliding motility.","evidence":"Traction force microscopy and laser tweezers on tlp- P. berghei sporozoites","pmids":["40716091"],"confidence":"Medium","gaps":["Does not resolve how TREP surface engagement is transduced into traction","Single lab, single study"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"The extracellular ligand(s) bound by the TREP TSR domain and the molecular basis distinguishing its traversal role from invasion remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No host or substrate receptor identified for the TSR domain","No structural model of TREP","Functional relationship with TRAP and S6 not mechanistically resolved"],"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Glideosome (actin-myosin motor coupling via aldolase-binding cytoplasmic tail) [#2]"],"partners":["ALDOLASE (BINDS TREP CYTOPLASMIC TAIL) [#2]","POFUT2 (O-FUCOSYLATES TREP TSR DOMAIN FOR TRAFFICKING/STABILITY) [#7]","FUNCTIONAL COOPERATION WITH TRAP AND S6 IN ADHESION [#4]"],"other_free_text":["TRAP-family transmembrane protein with a single TSR extracellular domain and a short cytoplasmic tail [#0].","Expressed predominantly in oocyst-stage sporozoites, contrasting with TRAP in salivary gland sporozoites [#1].","Loss of TREP impairs gliding motility, salivary gland invasion, cell traversal, adhesion, traction force, and in vivo infectivity, but not in vitro hepatocyte invasion [#0, #3, #4, #6, #8]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"9267031","id":"PMC_9267031","title":"TRAP is necessary for gliding motility and infectivity of plasmodium sporozoites.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9267031","citation_count":508,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TRAP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28422178","id":"PMC_28422178","title":"Enhancing protective 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Targeted disruption of the TREP gene in P. berghei sporozoites resulted in a highly diminished capacity to invade mosquito salivary glands and a severe defect in gliding motility, establishing that TREP is necessary for sporozoite gliding motility in the mosquito.\",\n      \"method\": \"Gene disruption (targeted gene knockout) in P. berghei; gliding motility assays; salivary gland invasion assays\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function genetic knockout with two distinct phenotypic readouts (gliding motility and salivary gland invasion) in a single focused study\",\n      \"pmids\": [\"19000911\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TREP (PF3D7_1442600) is expressed predominantly in oocyst-stage sporozoites (transcript level analysis by qRT-PCR), distinguishing its expression pattern from TRAP, which is expressed in salivary gland sporozoites.\",\n      \"method\": \"Quantitative reverse transcription PCR (qRT-PCR) of stage-specific transcripts\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (qRT-PCR), localization/expression without direct functional follow-up beyond the KO phenotype\",\n      \"pmids\": [\"19000911\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TREP (PF3D7_1442600/TLP) binds aldolase via its cytoplasmic tail, demonstrating that it couples to the actin-myosin motor machinery in the same manner as other TRAP family invasins. Genetic complementation showed the cytoplasmic tail of TREP can substitute for that of TRAP.\",\n      \"method\": \"Aldolase binding assay (in vitro pulldown); genetic complementation test in P. berghei\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assay combined with genetic complementation, two orthogonal methods in single study\",\n      \"pmids\": [\"18441124\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Targeted disruption of the TREP (PF3D7_1442600/TLP) gene in P. berghei resulted in decreased capacity for cell traversal by sporozoites and reduced infectivity in vivo, while in vitro sporozoite motility and hepatocyte invasion were unaffected, indicating a specific role for TREP in tissue traversal.\",\n      \"method\": \"Targeted gene disruption; in vivo infectivity assay; cell traversal assay; in vitro gliding motility and hepatocyte invasion assays\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple defined phenotypic readouts distinguishing traversal from motility and invasion\",\n      \"pmids\": [\"18346224\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TREP (PF3D7_1442600/TLP) was found to play a specific role in sporozoite adhesion under static conditions; tlp− sporozoites moved 4 times less efficiently than wild-type sporozoites, as shown by total internal reflection fluorescence (TIRF) microscopy and flow-based adhesion assays. TREP acts in concert with TRAP and S6 to organize efficient adhesion prior to initiating motility.\",\n      \"method\": \"Total internal reflection fluorescence (TIRF) microscopy; sporozoite adhesion assays under flow and static conditions; tlp− mutant P. berghei sporozoites\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging with genetic mutants and two experimental conditions (static vs. flow), single lab\",\n      \"pmids\": [\"20159960\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TREP (PF3D7_1442600/TLP)-deficient sporozoites show impaired adhesion resulting in altered migration patterns in complex environments. tlp− sporozoite speed and force generation are reduced, and the correlation between persistence length and dispersal breaks down, suggesting TREP contributes to environmental guidance of sporozoite migration.\",\n      \"method\": \"In vivo imaging in micro-fabricated obstacle arrays and skin; comparison of tlp− and wild-type sporozoite trajectories\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of KO parasites in defined environments, single lab, two experimental settings\",\n      \"pmids\": [\"21698220\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TREP (PF3D7_1442600/TLP) knockout sporozoites are defective in cell traversal: they fail to traverse MDCK monolayers and are retained inside the MDCK cytoplasm, providing direct evidence for a role of TREP in cell traversal distinct from invasion.\",\n      \"method\": \"Cell traversal assay through MDCK monolayers; fluorescent dye retention assay; tlp KO P. berghei sporozoites\",\n      \"journal\": \"Journal of immunological methods\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO, single cell traversal assay with direct imaging evidence, single lab\",\n      \"pmids\": [\"22306356\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Protein O-fucosylation of TREP (PF3D7_1442600) by the Plasmodium protein O-fucosyltransferase POFUT2 is required for correct trafficking and stability of TREP (a TSR domain-bearing protein). POFUT2-deficient P. falciparum parasites show destabilization and incorrect trafficking of TSR-bearing proteins including TREP, with downstream defects in gliding motility, cell traversal, and hepatocyte invasion.\",\n      \"method\": \"Genetic disruption of POFUT2; protein stability/trafficking assays; life cycle phenotyping (gliding motility, cell traversal, hepatocyte invasion)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple orthogonal functional assays; TREP is one of several TSR proteins affected, so direct attribution to TREP specifically is partially inferred\",\n      \"pmids\": [\"28916755\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TREP (PF3D7_1442600/TLP)-deficient sporozoites generate lower traction forces on both dorsal and ventral surfaces compared to wild-type, as measured by laser tweezers and traction force microscopy. This demonstrates that TREP is an important element of the force-generating machinery during sporozoite gliding motility.\",\n      \"method\": \"Traction force microscopy; laser tweezers; tlp− mutant P. berghei sporozoites\",\n      \"journal\": \"Journal of microscopy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — quantitative biophysical assays (traction force microscopy and optical tweezers) with genetic KO, single lab, single study\",\n      \"pmids\": [\"40716091\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glycosylation of P. falciparum TRAP's TSR domain (O-fucosylation at Thr256 and C-mannosylation at Trp250) is critical for TRAP protein abundance and function. CRISPR/Cas9 glyco-null mutants (T256A and W250F) of PfTRAP showed dramatically reduced TRAP protein levels despite normal transcript levels, and were unable to productively colonize mosquito salivary glands and were severely impaired in gliding motility and hepatocyte invasion — phenotypes comparable to TRAP knockout. Note: this finding is for PfTRAP (TRAP, a different gene), not PF3D7_1442600/TREP.\",\n      \"method\": \"CRISPR/Cas9 site-directed mutagenesis; protein abundance analysis; life cycle fitness assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Excluded from TREP discoveries — this finding is about PfTRAP (a different gene), not PF3D7_1442600/TREP\",\n      \"pmids\": [\"40667256\"],\n      \"is_preprint\": true,\n      \"attribution\": []\n    }\n  ],\n  \"current_model\": \"TREP (PF3D7_1442600) is a sporozoite-expressed TRAP-family transmembrane protein with a TSR-containing extracellular domain and a short cytoplasmic tail that binds aldolase, coupling it to the parasite actin-myosin motor; in P. berghei, loss of TREP causes severe defects in gliding motility, salivary gland invasion, cell traversal, and traction force generation, while having no detectable effect on in vitro hepatocyte invasion, indicating that TREP functions specifically in the force-transduction and tissue-traversal steps of sporozoite transmission in the mosquito.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TREP (PF3D7_1442600) is a TRAP-family transmembrane protein of Plasmodium sporozoites that couples surface adhesion to the actin-myosin motor to drive gliding motility and tissue traversal during transmission in the mosquito [#0, #2]. It possesses a large extracellular region containing a single thrombospondin type 1 repeat (TSR) domain and a short cytoplasmic tail that binds aldolase, linking it to the glideosome; this tail is functionally interchangeable with that of TRAP [#0, #2]. In P. berghei, TREP is expressed predominantly in oocyst-stage sporozoites, distinguishing it from TRAP, which acts in salivary gland sporozoites, and its disruption severely impairs gliding motility, salivary gland invasion, cell traversal, and in vivo infectivity while leaving in vitro hepatocyte invasion intact — placing TREP specifically in the adhesion, force-transduction, and traversal steps rather than the final invasion step [#0, #1, #3]. TREP contributes to substrate adhesion and to the traction forces sporozoites generate on both dorsal and ventral surfaces, so its loss reduces sporozoite speed, force generation, and environmental guidance during migration [#4, #5, #8]. As a TSR-bearing protein, TREP requires O-fucosylation by the protein O-fucosyltransferase POFUT2 for correct trafficking and stability [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"It was unknown how TREP couples to the parasite invasion machinery; showing that its cytoplasmic tail binds aldolase and can substitute for the TRAP tail established that TREP links surface adhesion to the actin-myosin motor like other TRAP-family invasins.\",\n      \"evidence\": \"In vitro aldolase pulldown plus genetic complementation of TRAP by the TREP tail in P. berghei\",\n      \"pmids\": [\"18441124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the extracellular ligand engaged by the TSR domain\", \"Does not resolve how tail-motor coupling is regulated during motility\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The role of the traversal/adhesion step versus final invasion was unresolved; TREP disruption impaired cell traversal and in vivo infectivity but not in vitro hepatocyte invasion, isolating TREP function to tissue traversal rather than invasion.\",\n      \"evidence\": \"Targeted gene disruption with cell traversal, in vivo infectivity, and hepatocyte invasion assays in P. berghei\",\n      \"pmids\": [\"18346224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the traversal defect not defined\", \"Does not explain why invasion is spared\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"TREP's stage of action and requirement for motility were unknown; knockout established it as necessary for gliding motility and salivary gland invasion, and qRT-PCR placed its expression in oocyst-stage sporozoites, distinguishing it from TRAP.\",\n      \"evidence\": \"Targeted knockout with gliding and salivary gland invasion assays plus stage-specific qRT-PCR in P. berghei (and P. falciparum expression)\",\n      \"pmids\": [\"19000911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcript-level expression not corroborated at protein level in this study\", \"Functional division of labor with TRAP not mechanistically dissected\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether TREP acts before or during motility was unclear; live imaging showed tlp- sporozoites adhere poorly under static conditions, establishing that TREP organizes efficient adhesion in concert with TRAP and S6 prior to motility initiation.\",\n      \"evidence\": \"TIRF microscopy and static/flow adhesion assays with tlp- P. berghei sporozoites\",\n      \"pmids\": [\"20159960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve the adhesive ligand or receptor engaged\", \"Relative contributions of TREP, TRAP, and S6 not quantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"It was unknown whether TREP influences directional migration in tissue; imaging in obstacle arrays and skin showed tlp- sporozoites have reduced speed and force and lose the persistence-dispersal correlation, indicating TREP contributes to environmental guidance of migration.\",\n      \"evidence\": \"In vivo imaging of tlp- versus wild-type sporozoite trajectories in micro-fabricated arrays and skin\",\n      \"pmids\": [\"21698220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking adhesion to trajectory guidance not defined\", \"Force reduction not directly measured biophysically here\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Direct evidence for TREP in traversal (versus mere motility loss) was needed; knockout sporozoites failed to traverse MDCK monolayers and were retained in the cytoplasm, confirming a traversal-specific role.\",\n      \"evidence\": \"MDCK monolayer traversal and dye-retention assays with tlp knockout P. berghei sporozoites\",\n      \"pmids\": [\"22306356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the molecular effector of cell exit\", \"Single traversal system\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"How TREP achieves stability and surface trafficking was unknown; loss of POFUT2 destabilized and mistrafficked TSR-bearing proteins including TREP, establishing O-fucosylation as a post-translational requirement for TREP maturation.\",\n      \"evidence\": \"Genetic disruption of POFUT2 with protein stability/trafficking and life-cycle phenotyping in P. falciparum and P. berghei\",\n      \"pmids\": [\"28916755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TREP is one of several affected TSR proteins, so TREP-specific effect is partly inferred\", \"Fucosylation site on TREP not mapped in this study\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether TREP contributes to physical force generation was untested; biophysical measurement showed tlp- sporozoites generate lower traction forces on both surfaces, placing TREP within the force-generating machinery of gliding motility.\",\n      \"evidence\": \"Traction force microscopy and laser tweezers on tlp- P. berghei sporozoites\",\n      \"pmids\": [\"40716091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve how TREP surface engagement is transduced into traction\", \"Single lab, single study\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The extracellular ligand(s) bound by the TREP TSR domain and the molecular basis distinguishing its traversal role from invasion remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No host or substrate receptor identified for the TSR domain\", \"No structural model of TREP\", \"Functional relationship with TRAP and S6 not mechanistically resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0051015\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071965\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0007155\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [\n      \"Glideosome (actin-myosin motor coupling via aldolase-binding cytoplasmic tail) [#2]\"\n    ],\n    \"partners\": [\n      \"Aldolase (binds TREP cytoplasmic tail) [#2]\",\n      \"POFUT2 (O-fucosylates TREP TSR domain for trafficking/stability) [#7]\",\n      \"Functional cooperation with TRAP and S6 in adhesion [#4]\"\n    ],\n    \"other_free_text\": [\n      \"TRAP-family transmembrane protein with a single TSR extracellular domain and a short cytoplasmic tail [#0].\",\n      \"Expressed predominantly in oocyst-stage sporozoites, contrasting with TRAP in salivary gland sporozoites [#1].\",\n      \"Loss of TREP impairs gliding motility, salivary gland invasion, cell traversal, adhesion, traction force, and in vivo infectivity, but not in vitro hepatocyte invasion [#0, #3, #4, #6, #8].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1442600","name":null,"product":"TRAP-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1306500","name":null,"product":"TRAP-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1239700","name":null,"product":"TRAP-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"TREP","evaluation":null}