{"gene":"TG_289620","gene_symbol":"CPC1","run_date":"2026-09-08T14:08:30","timeline":{"discoveries":[{"year":2006,"finding":"TgCPC1 is a cathepsin C exopeptidase that removes dipeptides from unblocked N-terminal substrates; it localizes to dense granules (constitutive secretory vesicles) in tachyzoites and is required for peptide degradation in the parasitophorous vacuole, as shown by complete inhibition of beta-lactamase degradation with a cathepsin C inhibitor (Gly-Phe-dimethylketone).","method":"Targeted gene disruption, specific enzyme inhibitor (Gly-Phe-dimethylketone), transgenic beta-lactamase reporter assay in parasitophorous vacuole, immunolocalization to dense granules, real-time PCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, specific inhibitor assay, organelle localization, and functional reporter assay in one study with multiple orthogonal methods","pmids":["17164247"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2006,"finding":"Targeted disruption of TgCPC1 does not affect tachyzoite invasion or growth, because TgCPC2 is upregulated and can substitute for TgCPC1 function.","method":"Targeted gene disruption (TgCPC1 knockout), intracellular growth and invasion assays, real-time PCR of TgCPC2 expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with phenotypic readout and compensatory gene expression analysis, single lab","pmids":["17164247"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2008,"finding":"TgCPC1 and TgCPC2 are trafficked through dense granules to the parasitophorous vacuole where they degrade peptides (confirmatory localization finding from a subsequent study).","method":"Subcellular fractionation/immunolocalization (referenced as prior characterization)","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — referenced result from prior work, corroborated in a second publication","pmids":["19111576"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"finding":"CPC1 protein suppresses NF-κB activation at or downstream of p65, reducing pro-inflammatory cytokine production (IL-1, IL-8, IL-6, IL-12, TNF-α), and operates through positive upregulation of the HIF-1α/EPO axis; knockdown of EPO or restriction of HIF-1α partially eliminated CPC1-mediated NF-κB suppression. CPC1 protein was found to reside primarily in the cytoplasm of host cells.","method":"Overexpression/knockdown of CPC1, western blot for phospho-p65, dual-luciferase reporter assays for HIF-1α and NF-κB, RNA sequencing, cytokine measurements, EPO/HIF-1α knockdown epistasis","journal":"Acta tropica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, epistasis knockdown, western blot, RNA-seq) in single lab","pmids":["31004564"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"TgCPC1 localizes to the endosome-like compartment (ELC) and mediates the final trimming (post-translational processing) of micronemal effectors within the secretory pathway; genetic deletion of TgCPC1 causes defects in invasion, egress, and migration. Critically, TgCPC1 deletion completely blocks activation of subtilisin-like protease 1 (TgSUB1), which globally impairs surface trimming of micronemal invasion and egress effectors.","method":"Genetic deletion of TgCPC1, immunolocalization to ELC, invasion/egress/migration assays, western blot analysis of micronemal protein maturation and TgSUB1 activation","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal functional assays (invasion, egress, migration), protein maturation analysis, and localization; peer-reviewed and replicated from preprint","pmids":["37326431"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"TgCPC1 is not efficiently inhibited by the chemical inhibitor targeting its malarial (Plasmodium) ortholog, indicating structural differences between apicomplexan cathepsin C orthologs.","method":"Pharmacological inhibitor assay comparing TgCPC1 vs. malarial CPC inhibitor","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct inhibitor assay demonstrating species-specific pharmacology, single lab","pmids":["37326431"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"TgCPC1 is a cathepsin C dipeptidyl exopeptidase that localizes to the endosome-like compartment (ELC) in tachyzoites, where it processes micronemal invasion/egress effectors and is essential for the full activation of the surface protease TgSUB1; it also traffics through dense granules to the parasitophorous vacuole to degrade peptides, and can suppress host NF-κB signaling via upregulation of the HIF-1α/EPO axis, with its loss causing defects in invasion, egress, and migration compensated in part by upregulation of TgCPC2."},"narrative":{"mechanistic_narrative":"TgCPC1 is a cathepsin C dipeptidyl exopeptidase of Toxoplasma gondii that removes dipeptides from unblocked N-terminal substrates and functions in the parasite's secretory and endolysosomal pathway to process invasion/egress effectors [PMID:17164247, PMID:37326431]. Within tachyzoites it localizes to the endosome-like compartment (ELC), where it mediates the final trimming of micronemal effectors; its deletion completely blocks activation of the surface subtilisin-like protease TgSUB1, globally impairing effector maturation and producing defects in invasion, egress, and migration [PMID:37326431]. TgCPC1 also traffics through dense granules to the parasitophorous vacuole, where it and its paralog TgCPC2 degrade peptides; loss of TgCPC1 alone is phenotypically buffered by compensatory upregulation of TgCPC2 [PMID:17164247]. Beyond its parasite-intrinsic protease role, CPC1 protein can act in host cells to suppress NF-κB activation at or downstream of p65 through positive regulation of the HIF-1α/EPO axis, dampening pro-inflammatory cytokine production [PMID:31004564]. TgCPC1 is resistant to a chemical inhibitor active against its malarial ortholog, indicating structural divergence among apicomplexan cathepsin C enzymes [PMID:37326431].","teleology":[{"year":2006,"claim":"Established TgCPC1's enzymatic identity and cellular role: whether the parasite encodes a functional dipeptidyl exopeptidase and where it acts was unknown, and this showed it is a cathepsin C required for peptide degradation in the parasitophorous vacuole.","evidence":"Targeted gene disruption, cathepsin C inhibitor (Gly-Phe-dimethylketone), transgenic beta-lactamase reporter in the parasitophorous vacuole, and dense-granule immunolocalization in tachyzoites","pmids":["17164247"],"confidence":"High","gaps":["Physiological substrates beyond the reporter not identified","Mechanism of trafficking to dense granules not defined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2006,"claim":"Addressed why TgCPC1 loss is tolerated: knockout did not impair invasion or growth because the paralog TgCPC2 was upregulated and could substitute, revealing functional redundancy.","evidence":"TgCPC1 knockout with intracellular growth/invasion assays and real-time PCR of TgCPC2 expression","pmids":["17164247"],"confidence":"Medium","gaps":["Direct proof of TgCPC2 functional substitution (rescue) not shown","Whether double knockout is lethal untested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2008,"claim":"Corroborated the dense-granule/parasitophorous vacuole trafficking route for TgCPC1 and TgCPC2 in a second study.","evidence":"Subcellular fractionation/immunolocalization referenced from prior characterization","pmids":["19111576"],"confidence":"Medium","gaps":["Referenced rather than newly generated data","Does not define the sorting signals or machinery"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"claim":"Extended CPC1's role to host-directed immune modulation: it was unknown whether the protein influences host inflammation, and this showed it suppresses NF-κB at or downstream of p65 via the HIF-1α/EPO axis.","evidence":"Overexpression/knockdown of CPC1, phospho-p65 western blot, HIF-1α/NF-κB dual-luciferase reporters, RNA-seq, cytokine measurements, and EPO/HIF-1α knockdown epistasis; CPC1 detected in host cell cytoplasm","pmids":["31004564"],"confidence":"Medium","gaps":["Direct molecular target linking CPC1 protease activity to HIF-1α/EPO not identified","Cytoplasmic host localization mechanism unexplained","Whether the exopeptidase activity is required for NF-κB suppression untested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"Redefined TgCPC1's core parasite function: it localizes to the endosome-like compartment and its deletion completely blocks TgSUB1 activation, placing it upstream of surface effector maturation and explaining invasion, egress, and migration defects.","evidence":"Genetic deletion, ELC immunolocalization, invasion/egress/migration assays, and western blot analysis of micronemal protein maturation and TgSUB1 activation","pmids":["37326431"],"confidence":"High","gaps":["Direct enzyme-substrate relationship between TgCPC1 and TgSUB1 propeptide not demonstrated","Reconciliation of ELC vs. dense-granule/PV localization not resolved","Full effector substrate set not enumerated"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"Demonstrated pharmacological divergence: TgCPC1 resists an inhibitor of its malarial ortholog, indicating structural differences relevant to species-selective drug targeting.","evidence":"Pharmacological inhibitor assay comparing TgCPC1 against a malarial CPC inhibitor","pmids":["37326431"],"confidence":"Medium","gaps":["No structural model of TgCPC1 provided","Basis of inhibitor resistance at the active site not defined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"How TgCPC1's ELC-localized protease activity mechanistically triggers TgSUB1 activation, and how this parasite-intrinsic role integrates with the reported host cytoplasmic NF-κB suppression, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct biochemical demonstration of TgSUB1 propeptide processing by TgCPC1","Localization discrepancies (ELC vs. dense granule/PV vs. host cytoplasm) unreconciled","No structural characterization"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["TGSUB1 (SUBTILISIN-LIKE PROTEASE 1) — ACTIVATION COMPLETELY BLOCKED BY TGCPC1 DELETION [#4]","TGCPC2 — PARALOGOUS CATHEPSIN C, CO-TRAFFICKED AND FUNCTIONALLY COMPENSATORY [#1, #2]"],"other_free_text":["Removes dipeptides from unblocked N-terminal substrates; not inhibited by the malarial CPC inhibitor, indicating structural divergence among apicomplexan orthologs [#5].","Reported to reside primarily in the host cell cytoplasm when acting to suppress NF-κB via the HIF-1α/EPO axis [#3], a localization distinct from its parasite ELC/dense-granule/PV distribution."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"17164247","id":"PMC_17164247","title":"Cathepsin Cs are key for the intracellular survival of the protozoan parasite, Toxoplasma gondii.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17164247","citation_count":46,"is_preprint":false},{"pmid":"19111576","id":"PMC_19111576","title":"The cathepsin L of Toxoplasma gondii (TgCPL) and its endogenous macromolecular inhibitor, toxostatin.","date":"2008","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/19111576","citation_count":36,"is_preprint":false},{"pmid":"21660658","id":"PMC_21660658","title":"Cathepsin proteases in Toxoplasma gondii.","date":"2011","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21660658","citation_count":33,"is_preprint":false},{"pmid":"29103265","id":"PMC_29103265","title":"DNA Vaccines Encoding Toxoplasma gondii Cathepsin C 1 Induce Protection against Toxoplasmosis in Mice.","date":"2017","source":"The Korean journal of parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/29103265","citation_count":12,"is_preprint":false},{"pmid":"31004564","id":"PMC_31004564","title":"Toxoplasma gondii Cathepsin C1 inhibits NF-κB signalling through the positive regulation of the HIF-1α/EPO axis.","date":"2019","source":"Acta tropica","url":"https://pubmed.ncbi.nlm.nih.gov/31004564","citation_count":11,"is_preprint":false},{"pmid":"37326431","id":"PMC_37326431","title":"A cathepsin C-like protease mediates the post-translation modification of Toxoplasma gondii secretory proteins for optimal invasion and egress.","date":"2023","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/37326431","citation_count":4,"is_preprint":false},{"pmid":"36712013","id":"PMC_36712013","title":"A cathepsin C-like protease post-translationally modifies Toxoplasma gondii secretory proteins for optimal invasion and egress.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36712013","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6524,"output_tokens":1723,"usd":0.022708,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6947,"output_tokens":3254,"usd":0.058042,"stage2_stop_reason":"end_turn"},"total_usd":0.08075,"stage1_batch_id":"msgbatch_015xmQKDRqnTh9anE4m7LiD6","stage2_batch_id":"msgbatch_01JLpkFTVhoQBNgqHCKFrVVU","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"TgCPC1 is a cathepsin C exopeptidase that removes dipeptides from unblocked N-terminal substrates; it localizes to dense granules (constitutive secretory vesicles) in tachyzoites and is required for peptide degradation in the parasitophorous vacuole, as shown by complete inhibition of beta-lactamase degradation with a cathepsin C inhibitor (Gly-Phe-dimethylketone).\",\n      \"method\": \"Targeted gene disruption, specific enzyme inhibitor (Gly-Phe-dimethylketone), transgenic beta-lactamase reporter assay in parasitophorous vacuole, immunolocalization to dense granules, real-time PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, specific inhibitor assay, organelle localization, and functional reporter assay in one study with multiple orthogonal methods\",\n      \"pmids\": [\"17164247\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Targeted disruption of TgCPC1 does not affect tachyzoite invasion or growth, because TgCPC2 is upregulated and can substitute for TgCPC1 function.\",\n      \"method\": \"Targeted gene disruption (TgCPC1 knockout), intracellular growth and invasion assays, real-time PCR of TgCPC2 expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with phenotypic readout and compensatory gene expression analysis, single lab\",\n      \"pmids\": [\"17164247\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TgCPC1 and TgCPC2 are trafficked through dense granules to the parasitophorous vacuole where they degrade peptides (confirmatory localization finding from a subsequent study).\",\n      \"method\": \"Subcellular fractionation/immunolocalization (referenced as prior characterization)\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — referenced result from prior work, corroborated in a second publication\",\n      \"pmids\": [\"19111576\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPC1 protein suppresses NF-κB activation at or downstream of p65, reducing pro-inflammatory cytokine production (IL-1, IL-8, IL-6, IL-12, TNF-α), and operates through positive upregulation of the HIF-1α/EPO axis; knockdown of EPO or restriction of HIF-1α partially eliminated CPC1-mediated NF-κB suppression. CPC1 protein was found to reside primarily in the cytoplasm of host cells.\",\n      \"method\": \"Overexpression/knockdown of CPC1, western blot for phospho-p65, dual-luciferase reporter assays for HIF-1α and NF-κB, RNA sequencing, cytokine measurements, EPO/HIF-1α knockdown epistasis\",\n      \"journal\": \"Acta tropica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, epistasis knockdown, western blot, RNA-seq) in single lab\",\n      \"pmids\": [\"31004564\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TgCPC1 localizes to the endosome-like compartment (ELC) and mediates the final trimming (post-translational processing) of micronemal effectors within the secretory pathway; genetic deletion of TgCPC1 causes defects in invasion, egress, and migration. Critically, TgCPC1 deletion completely blocks activation of subtilisin-like protease 1 (TgSUB1), which globally impairs surface trimming of micronemal invasion and egress effectors.\",\n      \"method\": \"Genetic deletion of TgCPC1, immunolocalization to ELC, invasion/egress/migration assays, western blot analysis of micronemal protein maturation and TgSUB1 activation\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal functional assays (invasion, egress, migration), protein maturation analysis, and localization; peer-reviewed and replicated from preprint\",\n      \"pmids\": [\"37326431\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TgCPC1 is not efficiently inhibited by the chemical inhibitor targeting its malarial (Plasmodium) ortholog, indicating structural differences between apicomplexan cathepsin C orthologs.\",\n      \"method\": \"Pharmacological inhibitor assay comparing TgCPC1 vs. malarial CPC inhibitor\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct inhibitor assay demonstrating species-specific pharmacology, single lab\",\n      \"pmids\": [\"37326431\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"TgCPC1 is a cathepsin C dipeptidyl exopeptidase that localizes to the endosome-like compartment (ELC) in tachyzoites, where it processes micronemal invasion/egress effectors and is essential for the full activation of the surface protease TgSUB1; it also traffics through dense granules to the parasitophorous vacuole to degrade peptides, and can suppress host NF-κB signaling via upregulation of the HIF-1α/EPO axis, with its loss causing defects in invasion, egress, and migration compensated in part by upregulation of TgCPC2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TgCPC1 is a cathepsin C dipeptidyl exopeptidase of Toxoplasma gondii that removes dipeptides from unblocked N-terminal substrates and functions in the parasite's secretory and endolysosomal pathway to process invasion/egress effectors [#0, #4]. Within tachyzoites it localizes to the endosome-like compartment (ELC), where it mediates the final trimming of micronemal effectors; its deletion completely blocks activation of the surface subtilisin-like protease TgSUB1, globally impairing effector maturation and producing defects in invasion, egress, and migration [#4]. TgCPC1 also traffics through dense granules to the parasitophorous vacuole, where it and its paralog TgCPC2 degrade peptides; loss of TgCPC1 alone is phenotypically buffered by compensatory upregulation of TgCPC2 [#0, #1]. Beyond its parasite-intrinsic protease role, CPC1 protein can act in host cells to suppress NF-\\u03baB activation at or downstream of p65 through positive regulation of the HIF-1\\u03b1/EPO axis, dampening pro-inflammatory cytokine production [#3]. TgCPC1 is resistant to a chemical inhibitor active against its malarial ortholog, indicating structural divergence among apicomplexan cathepsin C enzymes [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established TgCPC1's enzymatic identity and cellular role: whether the parasite encodes a functional dipeptidyl exopeptidase and where it acts was unknown, and this showed it is a cathepsin C required for peptide degradation in the parasitophorous vacuole.\",\n      \"evidence\": \"Targeted gene disruption, cathepsin C inhibitor (Gly-Phe-dimethylketone), transgenic beta-lactamase reporter in the parasitophorous vacuole, and dense-granule immunolocalization in tachyzoites\",\n      \"pmids\": [\"17164247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates beyond the reporter not identified\", \"Mechanism of trafficking to dense granules not defined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Addressed why TgCPC1 loss is tolerated: knockout did not impair invasion or growth because the paralog TgCPC2 was upregulated and could substitute, revealing functional redundancy.\",\n      \"evidence\": \"TgCPC1 knockout with intracellular growth/invasion assays and real-time PCR of TgCPC2 expression\",\n      \"pmids\": [\"17164247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proof of TgCPC2 functional substitution (rescue) not shown\", \"Whether double knockout is lethal untested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Corroborated the dense-granule/parasitophorous vacuole trafficking route for TgCPC1 and TgCPC2 in a second study.\",\n      \"evidence\": \"Subcellular fractionation/immunolocalization referenced from prior characterization\",\n      \"pmids\": [\"19111576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Referenced rather than newly generated data\", \"Does not define the sorting signals or machinery\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CPC1's role to host-directed immune modulation: it was unknown whether the protein influences host inflammation, and this showed it suppresses NF-\\u03baB at or downstream of p65 via the HIF-1\\u03b1/EPO axis.\",\n      \"evidence\": \"Overexpression/knockdown of CPC1, phospho-p65 western blot, HIF-1\\u03b1/NF-\\u03baB dual-luciferase reporters, RNA-seq, cytokine measurements, and EPO/HIF-1\\u03b1 knockdown epistasis; CPC1 detected in host cell cytoplasm\",\n      \"pmids\": [\"31004564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target linking CPC1 protease activity to HIF-1\\u03b1/EPO not identified\", \"Cytoplasmic host localization mechanism unexplained\", \"Whether the exopeptidase activity is required for NF-\\u03baB suppression untested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Redefined TgCPC1's core parasite function: it localizes to the endosome-like compartment and its deletion completely blocks TgSUB1 activation, placing it upstream of surface effector maturation and explaining invasion, egress, and migration defects.\",\n      \"evidence\": \"Genetic deletion, ELC immunolocalization, invasion/egress/migration assays, and western blot analysis of micronemal protein maturation and TgSUB1 activation\",\n      \"pmids\": [\"37326431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzyme-substrate relationship between TgCPC1 and TgSUB1 propeptide not demonstrated\", \"Reconciliation of ELC vs. dense-granule/PV localization not resolved\", \"Full effector substrate set not enumerated\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated pharmacological divergence: TgCPC1 resists an inhibitor of its malarial ortholog, indicating structural differences relevant to species-selective drug targeting.\",\n      \"evidence\": \"Pharmacological inhibitor assay comparing TgCPC1 against a malarial CPC inhibitor\",\n      \"pmids\": [\"37326431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TgCPC1 provided\", \"Basis of inhibitor resistance at the active site not defined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TgCPC1's ELC-localized protease activity mechanistically triggers TgSUB1 activation, and how this parasite-intrinsic role integrates with the reported host cytoplasmic NF-\\u03baB suppression, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical demonstration of TgSUB1 propeptide processing by TgCPC1\", \"Localization discrepancies (ELC vs. dense granule/PV vs. host cytoplasm) unreconciled\", \"No structural characterization\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004185\", \"supporting_discovery_ids\": [0, 4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0008234\", \"supporting_discovery_ids\": [0, 4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0070069\", \"supporting_discovery_ids\": [0, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0020003\", \"supporting_discovery_ids\": [0, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006508\", \"supporting_discovery_ids\": [0, 4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0043123\", \"supporting_discovery_ids\": [3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TgSUB1 (subtilisin-like protease 1) — activation completely blocked by TgCPC1 deletion [#4]\",\n      \"TgCPC2 — paralogous cathepsin C, co-trafficked and functionally compensatory [#1, #2]\"\n    ],\n    \"other_free_text\": [\n      \"Removes dipeptides from unblocked N-terminal substrates; not inhibited by the malarial CPC inhibitor, indicating structural divergence among apicomplexan orthologs [#5].\",\n      \"Reported to reside primarily in the host cell cytoplasm when acting to suppress NF-\\u03baB via the HIF-1\\u03b1/EPO axis [#3], a localization distinct from its parasite ELC/dense-granule/PV distribution.\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_289620","name":"CPC1","product":"cathepsin CPC1","uniprot_acc":"A0A125YXF9","chromosome":"TGME49_chrIX","start_pos":3350849},{"strain":"GT1","gene_id":"TGGT1_289620","name":null,"product":"cathepsin CPC1","uniprot_acc":null,"chromosome":"TGGT1_chrIX","start_pos":3159262},{"strain":"RH88","gene_id":"TGRH88_014370","name":null,"product":"cathepsin CPC1","uniprot_acc":null,"chromosome":"CM023090","start_pos":3415053},{"strain":"VEG","gene_id":"TGVEG_289620","name":null,"product":"cathepsin CPC1","uniprot_acc":"B9QE21","chromosome":"TGVEG_chrIX","start_pos":3385255}]}