{"gene":"FCN3","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"FCN3 encodes ficolin-3, a recognition molecule of the lectin pathway of complement; homozygosity for the FCN3 frameshift mutation (rs28357092/+1637delC) leads to undetectable serum ficolin-3 and deficiency in ficolin-3-dependent complement activation, establishing its essential role in lectin pathway initiation.","method":"Clinical characterization of homozygous patient with undetectable serum ficolin-3 plus complement activation assay","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional complement activation assay in a natural loss-of-function human model, replicated by recombinant protein studies in companion paper","pmids":["19535802"],"is_preprint":false},{"year":2008,"finding":"The FCN3+1637delC frameshift mutation distorts the C-terminal end of ficolin-3; recombinant protein produced from this allele demonstrates loss of pattern recognition capability, and in heterozygotes produces a truncated protein detectable by western blot alongside normal ficolin-3.","method":"Recombinant protein expression and characterization, SDS-PAGE/western blotting, ELISA","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — recombinant protein reconstitution with functional characterization, single lab with multiple orthogonal methods (ELISA, SDS-PAGE, western blot)","pmids":["18261799"],"is_preprint":false},{"year":2021,"finding":"Ectopic intracellular expression of FCN3 induces ER stress (unfolded protein response), cell cycle arrest and apoptosis in lung adenocarcinoma cells; the fibrinogen domain of FCN3, when localized to the ER, is both necessary and sufficient for apoptosis induction, whereas the secreted form of FCN3 has no effect on these cells.","method":"Ectopic overexpression in A549/H23 LUAD cell lines, ER stress inhibition rescue experiment, domain deletion analysis with fibrinogen domain constructs, cell cycle and apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain-of-function with defined cellular phenotype and domain mapping, single lab with multiple orthogonal methods","pmids":["33859174"],"is_preprint":false},{"year":2023,"finding":"In hepatocellular carcinoma cells, FCN3 physically binds SBDS (ribosome maturation factor), thereby modulating nuclear translocation of EIF6, inducing ribosomal stress and activating the p53 pathway; overexpression of FCN3 induces apoptosis and inhibits proliferation via this mechanism. YBX1 regulates FCN3 at the transcriptional and translational level, and a negative feedback loop involving p53, YBX1, and SBDS operates downstream of FCN3.","method":"Co-immunoprecipitation (FCN3-SBDS interaction), overexpression/knockdown in HCC cell lines, EIF6 nuclear translocation assays, p53 pathway reporter assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation identifying binding partner, functional pathway analysis, single lab","pmids":["36632465"],"is_preprint":false},{"year":2026,"finding":"The glycosyltransferase STT3A mediates N-glycosylation of FCN3 at Asn189, which disrupts FCN3's tumor-suppressive function in hepatocellular carcinoma; non-glycosylated FCN3 suppresses Treg activation and HCC progression by upregulating APC and thereby inhibiting Wnt/β-catenin signaling.","method":"Co-immunoprecipitation, lentiviral knockdown/overexpression of FCN3 and STT3A, glycosylation site validation (N189), in vivo xenograft mouse models, flow cytometry for Treg infiltration, immunofluorescence","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, site-specific glycosylation validation, in vivo rescue experiments; single lab but multiple orthogonal methods","pmids":["41493695"],"is_preprint":false}],"current_model":"FCN3 encodes ficolin-3, a secreted pattern recognition molecule that initiates the lectin complement pathway; a frameshift mutation abolishing its C-terminal domain causes complete complement lectin pathway deficiency in homozygotes. Intracellularly, the non-secreted fibrinogen domain of FCN3 can induce ER stress and apoptosis in cancer cells; in HCC, FCN3 suppresses tumor progression by binding SBDS to activate p53 signaling and by upregulating APC to inhibit Wnt/β-catenin, while STT3A-mediated N-glycosylation at Asn189 antagonizes these tumor-suppressive functions."},"narrative":{"mechanistic_narrative":"FCN3 encodes ficolin-3, a secreted pattern recognition molecule that initiates the lectin pathway of complement [PMID:19535802]. Homozygosity for the FCN3 +1637delC frameshift mutation distorts the protein's C-terminal end, abolishing pattern recognition; affected individuals have undetectable serum ficolin-3 and are deficient in ficolin-3-dependent complement activation, defining a complete lectin pathway deficiency [PMID:19535802, PMID:18261799]. Beyond its extracellular complement role, FCN3 has a context-dependent intracellular function in cancer cells: when retained in the ER, its fibrinogen domain is necessary and sufficient to trigger the unfolded protein response, cell cycle arrest, and apoptosis, whereas the secreted form is inert in this setting [PMID:33859174]. In hepatocellular carcinoma, intracellular FCN3 acts as a tumor suppressor by binding the ribosome maturation factor SBDS to modulate EIF6 nuclear translocation, inducing ribosomal stress and activating p53-dependent apoptosis [PMID:36632465], and by upregulating APC to inhibit Wnt/β-catenin signaling and suppress Treg activation [PMID:41493695]; STT3A-mediated N-glycosylation of FCN3 at Asn189 antagonizes these tumor-suppressive activities [PMID:41493695].","teleology":[{"year":2008,"claim":"Established that the FCN3 +1637delC frameshift produces a functionally defective protein, answering whether the mutation merely altered the sequence or abrogated the molecule's recognition activity.","evidence":"Recombinant expression of the mutant allele with ELISA, SDS-PAGE, and western blot, detecting a truncated protein in heterozygotes","pmids":["18261799"],"confidence":"High","gaps":["Did not establish the clinical/complement-activation consequence in vivo","Structural basis of how C-terminal distortion abolishes ligand binding not resolved"]},{"year":2009,"claim":"Defined ficolin-3 as an essential initiator of the lectin complement pathway by showing that its complete loss in a homozygous human ablates ficolin-3-dependent complement activation.","evidence":"Clinical characterization of a homozygous patient with undetectable serum ficolin-3 plus complement activation assays","pmids":["19535802"],"confidence":"High","gaps":["Specific microbial/molecular ligands recognized by ficolin-3 not enumerated here","Downstream effector partners of the activated lectin pathway not detailed"]},{"year":2021,"claim":"Revealed a non-complement, intracellular activity of FCN3 by demonstrating that its ER-localized fibrinogen domain drives ER stress and apoptosis, separating the secreted function from a cell-intrinsic pro-apoptotic one.","evidence":"Ectopic overexpression and domain-deletion analysis in LUAD cell lines with ER stress rescue and apoptosis/cell-cycle assays","pmids":["33859174"],"confidence":"Medium","gaps":["Mechanism by which the fibrinogen domain triggers the UPR not defined","Whether endogenous FCN3 is ever ER-retained physiologically unknown","Limited to two LUAD lines in a single lab"]},{"year":2023,"claim":"Identified a molecular partner and pathway for FCN3's tumor-suppressive effect, showing it binds SBDS to perturb EIF6 nuclear shuttling and activate p53, linking FCN3 to ribosomal stress signaling.","evidence":"Co-immunoprecipitation, overexpression/knockdown in HCC lines, EIF6 translocation and p53 reporter assays","pmids":["36632465"],"confidence":"Medium","gaps":["Single Co-IP-based interaction without reciprocal structural validation","Direct binding versus complex-mediated association not distinguished","p53-YBX1-SBDS feedback loop mapped only in HCC cell lines"]},{"year":2026,"claim":"Showed that a post-translational switch governs FCN3's anti-tumor activity, with STT3A-mediated N-glycosylation at Asn189 disabling its suppression of Wnt/β-catenin and Treg activation.","evidence":"Co-IP, site-specific N189 glycosylation validation, lentiviral knockdown/overexpression, xenograft models, and Treg flow cytometry","pmids":["41493695"],"confidence":"Medium","gaps":["Mechanism connecting FCN3 to APC upregulation not resolved","How glycosylation at N189 alters FCN3 localization or interactions unclear","Single-lab findings without independent replication"]},{"year":null,"claim":"How FCN3's canonical extracellular complement-initiating role mechanistically relates to its intracellular tumor-suppressive functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking secreted ficolin-3 and ER-retained pro-apoptotic FCN3","Physiological relevance of intracellular FCN3 outside cancer cell lines untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["SBDS","STT3A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75636","full_name":"Ficolin-3","aliases":["Collagen/fibrinogen domain-containing lectin 3 p35","Collagen/fibrinogen domain-containing protein 3","H-ficolin","Hakata antigen"],"length_aa":299,"mass_kda":32.9,"function":"Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:11907111, PubMed:15804047, PubMed:17215869, PubMed:26133042). Specifically recognizes and binds carbohydrates on the pathogen surface, activating the MASP1 serine protease and initiating the proteolytic cascade of the lectin complement pathway (PubMed:15804047, PubMed:17215869, PubMed:26133042). Specifically binds N-Acetylglucosamine (GlcNAc,) GalNAc (N-acetylgalactosamine) and D-fucose on the surface of pathogens, as well as mono/oligosaccharide and lipopolysaccharides from S.typhimurium and S.minnesota (PubMed:17215869)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/O75636/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FCN3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FCN3","total_profiled":1310},"omim":[{"mim_id":"614372","title":"MANNOSE-BINDING LECTIN DEFICIENCY; MBLD","url":"https://www.omim.org/entry/614372"},{"mim_id":"613860","title":"FICOLIN 3 DEFICIENCY","url":"https://www.omim.org/entry/613860"},{"mim_id":"604973","title":"FICOLIN 3; FCN3","url":"https://www.omim.org/entry/604973"},{"mim_id":"601624","title":"FICOLIN 2; FCN2","url":"https://www.omim.org/entry/601624"},{"mim_id":"601252","title":"FICOLIN 1; FCN1","url":"https://www.omim.org/entry/601252"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":260.7},{"tissue":"lung","ntpm":688.3}],"url":"https://www.proteinatlas.org/search/FCN3"},"hgnc":{"alias_symbol":["FCNH","HAKA1"],"prev_symbol":[]},"alphafold":{"accession":"O75636","domains":[{"cath_id":"3.90.215.10","chopping":"94-299","consensus_level":"medium","plddt":98.0377,"start":94,"end":299}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75636","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75636-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75636-F1-predicted_aligned_error_v6.png","plddt_mean":86.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FCN3","jax_strain_url":"https://www.jax.org/strain/search?query=FCN3"},"sequence":{"accession":"O75636","fasta_url":"https://rest.uniprot.org/uniprotkb/O75636.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75636/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75636"}},"corpus_meta":[{"pmid":"19535802","id":"PMC_19535802","title":"Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency.","date":"2009","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19535802","citation_count":136,"is_preprint":false},{"pmid":"19501910","id":"PMC_19501910","title":"MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement.","date":"2009","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19501910","citation_count":122,"is_preprint":false},{"pmid":"18261799","id":"PMC_18261799","title":"Characterization of a polymorphism in the coding sequence of FCN3 resulting in a Ficolin-3 (Hakata antigen) deficiency state.","date":"2008","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18261799","citation_count":109,"is_preprint":false},{"pmid":"33859174","id":"PMC_33859174","title":"FCN3 functions as a tumor suppressor of lung adenocarcinoma through induction of endoplasmic reticulum stress.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33859174","citation_count":33,"is_preprint":false},{"pmid":"22226667","id":"PMC_22226667","title":"H-ficolin (ficolin-3) concentrations and FCN3 gene polymorphism in neonates.","date":"2011","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22226667","citation_count":33,"is_preprint":false},{"pmid":"36632465","id":"PMC_36632465","title":"FCN3 inhibits the progression of hepatocellular carcinoma by suppressing SBDS-mediated blockade of the p53 pathway.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36632465","citation_count":23,"is_preprint":false},{"pmid":"28241035","id":"PMC_28241035","title":"Association of a new FCN3 haplotype with high ficolin-3 levels in leprosy.","date":"2017","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28241035","citation_count":20,"is_preprint":false},{"pmid":"26795763","id":"PMC_26795763","title":"Frequency and distribution of FCN2 and FCN3 functional variants among MBL2 genotypes.","date":"2016","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26795763","citation_count":8,"is_preprint":false},{"pmid":"36863704","id":"PMC_36863704","title":"Identification MNS1, FRZB, OGN, LUM, SERP1NA3 and FCN3 as the potential immune-related key genes involved in ischaemic cardiomyopathy by random forest and nomogram.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/36863704","citation_count":8,"is_preprint":false},{"pmid":"22471352","id":"PMC_22471352","title":"A common genetic variant of FCN3/CD164L2 is associated with essential hypertension in a Chinese population.","date":"2012","source":"Clinical and experimental hypertension (New York, N.Y. : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/22471352","citation_count":8,"is_preprint":false},{"pmid":"36569030","id":"PMC_36569030","title":"Effect of Polymorphisms in the FCN1, FCN2, and FCN3 Genes on the Susceptibility to Develop Rheumatoid Arthritis: A Systematic Review.","date":"2022","source":"International journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/36569030","citation_count":5,"is_preprint":false},{"pmid":"39717447","id":"PMC_39717447","title":"SMOC2, OGN, FCN3, and SERPINA3 could be biomarkers for the evaluation of acute decompensated heart failure caused by venous congestion.","date":"2024","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39717447","citation_count":2,"is_preprint":false},{"pmid":"41493695","id":"PMC_41493695","title":"STT3A-mediated FCN3 N-glycosylation promotes Treg cell activation to drive hepatocellular carcinoma progression via Wnt/β-catenin.","date":"2026","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/41493695","citation_count":0,"is_preprint":false},{"pmid":"35083404","id":"PMC_35083404","title":"Prevalence of the polymorphic H-f icolin (FCN3) genes and mannose-binding lectin-associated serine protease-2 (MASP2) in indigenous populations from the Russian Arctic regions.","date":"2021","source":"Vavilovskii zhurnal genetiki i selektsii","url":"https://pubmed.ncbi.nlm.nih.gov/35083404","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9073,"output_tokens":1416,"usd":0.02423,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8130,"output_tokens":2240,"usd":0.048325,"stage2_stop_reason":"end_turn"},"total_usd":0.072555,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"FCN3 encodes ficolin-3, a recognition molecule of the lectin pathway of complement; homozygosity for the FCN3 frameshift mutation (rs28357092/+1637delC) leads to undetectable serum ficolin-3 and deficiency in ficolin-3-dependent complement activation, establishing its essential role in lectin pathway initiation.\",\n      \"method\": \"Clinical characterization of homozygous patient with undetectable serum ficolin-3 plus complement activation assay\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional complement activation assay in a natural loss-of-function human model, replicated by recombinant protein studies in companion paper\",\n      \"pmids\": [\"19535802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The FCN3+1637delC frameshift mutation distorts the C-terminal end of ficolin-3; recombinant protein produced from this allele demonstrates loss of pattern recognition capability, and in heterozygotes produces a truncated protein detectable by western blot alongside normal ficolin-3.\",\n      \"method\": \"Recombinant protein expression and characterization, SDS-PAGE/western blotting, ELISA\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant protein reconstitution with functional characterization, single lab with multiple orthogonal methods (ELISA, SDS-PAGE, western blot)\",\n      \"pmids\": [\"18261799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ectopic intracellular expression of FCN3 induces ER stress (unfolded protein response), cell cycle arrest and apoptosis in lung adenocarcinoma cells; the fibrinogen domain of FCN3, when localized to the ER, is both necessary and sufficient for apoptosis induction, whereas the secreted form of FCN3 has no effect on these cells.\",\n      \"method\": \"Ectopic overexpression in A549/H23 LUAD cell lines, ER stress inhibition rescue experiment, domain deletion analysis with fibrinogen domain constructs, cell cycle and apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain-of-function with defined cellular phenotype and domain mapping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33859174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In hepatocellular carcinoma cells, FCN3 physically binds SBDS (ribosome maturation factor), thereby modulating nuclear translocation of EIF6, inducing ribosomal stress and activating the p53 pathway; overexpression of FCN3 induces apoptosis and inhibits proliferation via this mechanism. YBX1 regulates FCN3 at the transcriptional and translational level, and a negative feedback loop involving p53, YBX1, and SBDS operates downstream of FCN3.\",\n      \"method\": \"Co-immunoprecipitation (FCN3-SBDS interaction), overexpression/knockdown in HCC cell lines, EIF6 nuclear translocation assays, p53 pathway reporter assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation identifying binding partner, functional pathway analysis, single lab\",\n      \"pmids\": [\"36632465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The glycosyltransferase STT3A mediates N-glycosylation of FCN3 at Asn189, which disrupts FCN3's tumor-suppressive function in hepatocellular carcinoma; non-glycosylated FCN3 suppresses Treg activation and HCC progression by upregulating APC and thereby inhibiting Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, lentiviral knockdown/overexpression of FCN3 and STT3A, glycosylation site validation (N189), in vivo xenograft mouse models, flow cytometry for Treg infiltration, immunofluorescence\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, site-specific glycosylation validation, in vivo rescue experiments; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41493695\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FCN3 encodes ficolin-3, a secreted pattern recognition molecule that initiates the lectin complement pathway; a frameshift mutation abolishing its C-terminal domain causes complete complement lectin pathway deficiency in homozygotes. Intracellularly, the non-secreted fibrinogen domain of FCN3 can induce ER stress and apoptosis in cancer cells; in HCC, FCN3 suppresses tumor progression by binding SBDS to activate p53 signaling and by upregulating APC to inhibit Wnt/β-catenin, while STT3A-mediated N-glycosylation at Asn189 antagonizes these tumor-suppressive functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FCN3 encodes ficolin-3, a secreted pattern recognition molecule that initiates the lectin pathway of complement [#0]. Homozygosity for the FCN3 +1637delC frameshift mutation distorts the protein's C-terminal end, abolishing pattern recognition; affected individuals have undetectable serum ficolin-3 and are deficient in ficolin-3-dependent complement activation, defining a complete lectin pathway deficiency [#0, #1]. Beyond its extracellular complement role, FCN3 has a context-dependent intracellular function in cancer cells: when retained in the ER, its fibrinogen domain is necessary and sufficient to trigger the unfolded protein response, cell cycle arrest, and apoptosis, whereas the secreted form is inert in this setting [#2]. In hepatocellular carcinoma, intracellular FCN3 acts as a tumor suppressor by binding the ribosome maturation factor SBDS to modulate EIF6 nuclear translocation, inducing ribosomal stress and activating p53-dependent apoptosis [#3], and by upregulating APC to inhibit Wnt/\\u03b2-catenin signaling and suppress Treg activation [#4]; STT3A-mediated N-glycosylation of FCN3 at Asn189 antagonizes these tumor-suppressive activities [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that the FCN3 +1637delC frameshift produces a functionally defective protein, answering whether the mutation merely altered the sequence or abrogated the molecule's recognition activity.\",\n      \"evidence\": \"Recombinant expression of the mutant allele with ELISA, SDS-PAGE, and western blot, detecting a truncated protein in heterozygotes\",\n      \"pmids\": [\"18261799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not establish the clinical/complement-activation consequence in vivo\",\n        \"Structural basis of how C-terminal distortion abolishes ligand binding not resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined ficolin-3 as an essential initiator of the lectin complement pathway by showing that its complete loss in a homozygous human ablates ficolin-3-dependent complement activation.\",\n      \"evidence\": \"Clinical characterization of a homozygous patient with undetectable serum ficolin-3 plus complement activation assays\",\n      \"pmids\": [\"19535802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific microbial/molecular ligands recognized by ficolin-3 not enumerated here\",\n        \"Downstream effector partners of the activated lectin pathway not detailed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a non-complement, intracellular activity of FCN3 by demonstrating that its ER-localized fibrinogen domain drives ER stress and apoptosis, separating the secreted function from a cell-intrinsic pro-apoptotic one.\",\n      \"evidence\": \"Ectopic overexpression and domain-deletion analysis in LUAD cell lines with ER stress rescue and apoptosis/cell-cycle assays\",\n      \"pmids\": [\"33859174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which the fibrinogen domain triggers the UPR not defined\",\n        \"Whether endogenous FCN3 is ever ER-retained physiologically unknown\",\n        \"Limited to two LUAD lines in a single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a molecular partner and pathway for FCN3's tumor-suppressive effect, showing it binds SBDS to perturb EIF6 nuclear shuttling and activate p53, linking FCN3 to ribosomal stress signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown in HCC lines, EIF6 translocation and p53 reporter assays\",\n      \"pmids\": [\"36632465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP-based interaction without reciprocal structural validation\",\n        \"Direct binding versus complex-mediated association not distinguished\",\n        \"p53-YBX1-SBDS feedback loop mapped only in HCC cell lines\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that a post-translational switch governs FCN3's anti-tumor activity, with STT3A-mediated N-glycosylation at Asn189 disabling its suppression of Wnt/\\u03b2-catenin and Treg activation.\",\n      \"evidence\": \"Co-IP, site-specific N189 glycosylation validation, lentiviral knockdown/overexpression, xenograft models, and Treg flow cytometry\",\n      \"pmids\": [\"41493695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting FCN3 to APC upregulation not resolved\",\n        \"How glycosylation at N189 alters FCN3 localization or interactions unclear\",\n        \"Single-lab findings without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FCN3's canonical extracellular complement-initiating role mechanistically relates to its intracellular tumor-suppressive functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model linking secreted ficolin-3 and ER-retained pro-apoptotic FCN3\",\n        \"Physiological relevance of intracellular FCN3 outside cancer cell lines untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SBDS\", \"STT3A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}