{"gene":"BPIFB6","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2002,"finding":"BPIFB6 (BPIL3) was identified as a member of the lipid transfer/lipopolysaccharide binding protein (LT/LBP) gene family based on sequence homology, implying capacity for phospholipid and lipopolysaccharide binding; its exon/intron organization is highly conserved with BPI, suggesting evolution from a common ancestor.","method":"Sequence homology analysis and genomic structural comparison (exon/intron organization); chromosomal mapping to Chr 20q11","journal":"Immunogenetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/sequence-based inference only, no direct biochemical binding assay performed","pmids":["12185532"],"is_preprint":false},{"year":2016,"finding":"BPIFB6 localizes exclusively to the endoplasmic reticulum (ER), where it associates (forms complexes) with other members of the BPIFB family.","method":"Subcellular localization by fluorescence microscopy and co-localization/co-association assays (implied by ER localization and family member association statements)","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment reported in a focused mechanistic study, single lab, single method described in abstract","pmids":["26962226"],"is_preprint":false},{"year":2016,"finding":"RNAi-mediated silencing of BPIFB6 dramatically suppresses enterovirus (CVB, poliovirus, EV71) replication in a pan-viral manner, establishing BPIFB6 as a positive regulator of enterovirus replication.","method":"RNAi knockdown with viral replication readout (plaque/titer assays) across multiple enteroviruses","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype across multiple viruses, single lab","pmids":["26962226"],"is_preprint":false},{"year":2016,"finding":"Loss of BPIFB6 expression induces pronounced alterations in both retrograde and anterograde secretory pathway trafficking, correlating with dramatic fragmentation of the Golgi complex, identifying BPIFB6 as a key regulator of secretory pathway trafficking.","method":"RNAi knockdown followed by secretory pathway trafficking assays and Golgi morphology imaging","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (Golgi fragmentation, trafficking defects) using two orthogonal readouts, single lab","pmids":["26962226"],"is_preprint":false}],"current_model":"BPIFB6 is an ER-resident member of the BPI-fold/LT-LBP protein family that associates with other BPIFB family members and functions as a positive regulator of secretory pathway trafficking and Golgi complex integrity, such that its loss causes Golgi fragmentation and defects in anterograde/retrograde trafficking, thereby suppressing enterovirus replication."},"narrative":{"mechanistic_narrative":"BPIFB6 is an endoplasmic reticulum-resident member of the BPI-fold/lipid transfer-lipopolysaccharide binding protein (LT/LBP) family that functions as a positive regulator of secretory pathway trafficking and Golgi complex integrity [PMID:26962226]. It localizes exclusively to the ER, where it associates with other BPIFB family members [PMID:26962226]. Loss of BPIFB6 induces pronounced defects in both retrograde and anterograde secretory trafficking accompanied by dramatic Golgi fragmentation [PMID:26962226], and this disruption of the secretory pathway suppresses replication of multiple enteroviruses (coxsackievirus B, poliovirus, EV71) in a pan-viral manner, establishing BPIFB6 as a host factor required for enterovirus replication [PMID:26962226]. The molecular basis of its trafficking function and the lipid/LPS-binding capacity inferred from its family membership have not been directly characterized in the available corpus.","teleology":[{"year":2002,"claim":"Before any functional data existed, the question was what kind of protein BPIFB6 is; sequence and genomic analysis placed it in the LT/LBP family, framing an expectation of phospholipid/LPS-binding capacity.","evidence":"Sequence homology and exon/intron structural comparison with chromosomal mapping to 20q11","pmids":["12185532"],"confidence":"Low","gaps":["Family assignment is computational only — no direct lipid or LPS binding assay was performed","No cellular function or localization established at this stage"]},{"year":2016,"claim":"To define where BPIFB6 acts, localization and association studies showed it is an ER-resident protein that forms complexes with other BPIFB family members, anchoring its function to the early secretory pathway.","evidence":"Fluorescence microscopy localization and co-association assays in cultured cells","pmids":["26962226"],"confidence":"Medium","gaps":["Identity of the specific BPIFB partners and stoichiometry of the complexes not resolved","Single lab, single localization method"]},{"year":2016,"claim":"To test whether BPIFB6 has a cellular trafficking role, loss-of-function showed that its depletion fragments the Golgi and disrupts both anterograde and retrograde trafficking, establishing it as a regulator of secretory pathway integrity.","evidence":"RNAi knockdown with trafficking assays and Golgi morphology imaging","pmids":["26962226"],"confidence":"Medium","gaps":["The molecular mechanism linking an ER protein to Golgi integrity is unknown","No rescue or interactor mapping to explain how trafficking is controlled"]},{"year":2016,"claim":"To connect BPIFB6 to a biological outcome, silencing showed it is required for enterovirus replication across multiple viruses, identifying it as a host dependency factor likely acting through its secretory-pathway role.","evidence":"RNAi knockdown with viral titer/plaque readouts across CVB, poliovirus, and EV71","pmids":["26962226"],"confidence":"Medium","gaps":["Whether viral suppression is a direct consequence of Golgi/trafficking disruption versus another pathway is not formally separated","No direct interaction between BPIFB6 and viral proteins demonstrated"]},{"year":null,"claim":"The biochemical activity of BPIFB6 — whether it binds lipids or LPS as its family suggests, and how an ER protein controls Golgi morphology and trafficking — remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct lipid/LPS binding assay reported","No structural model or substrate identified","Mechanism coupling ER residence to Golgi integrity unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFQ5","full_name":"BPI fold-containing family B member 6","aliases":["Bactericidal/permeability-increasing protein-like 3"],"length_aa":453,"mass_kda":49.7,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8NFQ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BPIFB6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BPIFB6","total_profiled":1310},"omim":[{"mim_id":"614110","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY B, MEMBER 6; BPIFB6","url":"https://www.omim.org/entry/614110"},{"mim_id":"614108","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY B, MEMBER 2; BPIFB2","url":"https://www.omim.org/entry/614108"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"salivary gland","ntpm":3.2}],"url":"https://www.proteinatlas.org/search/BPIFB6"},"hgnc":{"alias_symbol":["LPLUNC6"],"prev_symbol":["BPIL3"]},"alphafold":{"accession":"Q8NFQ5","domains":[{"cath_id":"3.15.10.10","chopping":"28-188","consensus_level":"medium","plddt":83.8496,"start":28,"end":188},{"cath_id":"3.15.20.10","chopping":"227-235_248-451","consensus_level":"medium","plddt":93.937,"start":227,"end":451}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFQ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFQ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFQ5-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BPIFB6","jax_strain_url":"https://www.jax.org/strain/search?query=BPIFB6"},"sequence":{"accession":"Q8NFQ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFQ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFQ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFQ5"}},"corpus_meta":[{"pmid":"12185532","id":"PMC_12185532","title":"Three new human members of the lipid transfer/lipopolysaccharide binding protein family (LT/LBP).","date":"2002","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12185532","citation_count":45,"is_preprint":false},{"pmid":"26962226","id":"PMC_26962226","title":"BPIFB6 Regulates Secretory Pathway Trafficking and Enterovirus Replication.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26962226","citation_count":31,"is_preprint":false},{"pmid":"27529132","id":"PMC_27529132","title":"Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature.","date":"2016","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/27529132","citation_count":17,"is_preprint":false},{"pmid":"40473938","id":"PMC_40473938","title":"Identification of genetic biomarkers of blood cholesterol levels using whole gene pathogenicity modelling.","date":"2025","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/40473938","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4123,"output_tokens":909,"usd":0.013002,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7373,"output_tokens":1700,"usd":0.039683,"stage2_stop_reason":"end_turn"},"total_usd":0.052685,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"BPIFB6 (BPIL3) was identified as a member of the lipid transfer/lipopolysaccharide binding protein (LT/LBP) gene family based on sequence homology, implying capacity for phospholipid and lipopolysaccharide binding; its exon/intron organization is highly conserved with BPI, suggesting evolution from a common ancestor.\",\n      \"method\": \"Sequence homology analysis and genomic structural comparison (exon/intron organization); chromosomal mapping to Chr 20q11\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/sequence-based inference only, no direct biochemical binding assay performed\",\n      \"pmids\": [\"12185532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BPIFB6 localizes exclusively to the endoplasmic reticulum (ER), where it associates (forms complexes) with other members of the BPIFB family.\",\n      \"method\": \"Subcellular localization by fluorescence microscopy and co-localization/co-association assays (implied by ER localization and family member association statements)\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment reported in a focused mechanistic study, single lab, single method described in abstract\",\n      \"pmids\": [\"26962226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNAi-mediated silencing of BPIFB6 dramatically suppresses enterovirus (CVB, poliovirus, EV71) replication in a pan-viral manner, establishing BPIFB6 as a positive regulator of enterovirus replication.\",\n      \"method\": \"RNAi knockdown with viral replication readout (plaque/titer assays) across multiple enteroviruses\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype across multiple viruses, single lab\",\n      \"pmids\": [\"26962226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of BPIFB6 expression induces pronounced alterations in both retrograde and anterograde secretory pathway trafficking, correlating with dramatic fragmentation of the Golgi complex, identifying BPIFB6 as a key regulator of secretory pathway trafficking.\",\n      \"method\": \"RNAi knockdown followed by secretory pathway trafficking assays and Golgi morphology imaging\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (Golgi fragmentation, trafficking defects) using two orthogonal readouts, single lab\",\n      \"pmids\": [\"26962226\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BPIFB6 is an ER-resident member of the BPI-fold/LT-LBP protein family that associates with other BPIFB family members and functions as a positive regulator of secretory pathway trafficking and Golgi complex integrity, such that its loss causes Golgi fragmentation and defects in anterograde/retrograde trafficking, thereby suppressing enterovirus replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BPIFB6 is an endoplasmic reticulum-resident member of the BPI-fold/lipid transfer-lipopolysaccharide binding protein (LT/LBP) family that functions as a positive regulator of secretory pathway trafficking and Golgi complex integrity [#1, #3]. It localizes exclusively to the ER, where it associates with other BPIFB family members [#1]. Loss of BPIFB6 induces pronounced defects in both retrograde and anterograde secretory trafficking accompanied by dramatic Golgi fragmentation [#3], and this disruption of the secretory pathway suppresses replication of multiple enteroviruses (coxsackievirus B, poliovirus, EV71) in a pan-viral manner, establishing BPIFB6 as a host factor required for enterovirus replication [#2]. The molecular basis of its trafficking function and the lipid/LPS-binding capacity inferred from its family membership have not been directly characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Before any functional data existed, the question was what kind of protein BPIFB6 is; sequence and genomic analysis placed it in the LT/LBP family, framing an expectation of phospholipid/LPS-binding capacity.\",\n      \"evidence\": \"Sequence homology and exon/intron structural comparison with chromosomal mapping to 20q11\",\n      \"pmids\": [\n        \"12185532\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Family assignment is computational only \\u2014 no direct lipid or LPS binding assay was performed\",\n        \"No cellular function or localization established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To define where BPIFB6 acts, localization and association studies showed it is an ER-resident protein that forms complexes with other BPIFB family members, anchoring its function to the early secretory pathway.\",\n      \"evidence\": \"Fluorescence microscopy localization and co-association assays in cultured cells\",\n      \"pmids\": [\n        \"26962226\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the specific BPIFB partners and stoichiometry of the complexes not resolved\",\n        \"Single lab, single localization method\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To test whether BPIFB6 has a cellular trafficking role, loss-of-function showed that its depletion fragments the Golgi and disrupts both anterograde and retrograde trafficking, establishing it as a regulator of secretory pathway integrity.\",\n      \"evidence\": \"RNAi knockdown with trafficking assays and Golgi morphology imaging\",\n      \"pmids\": [\n        \"26962226\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular mechanism linking an ER protein to Golgi integrity is unknown\",\n        \"No rescue or interactor mapping to explain how trafficking is controlled\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To connect BPIFB6 to a biological outcome, silencing showed it is required for enterovirus replication across multiple viruses, identifying it as a host dependency factor likely acting through its secretory-pathway role.\",\n      \"evidence\": \"RNAi knockdown with viral titer/plaque readouts across CVB, poliovirus, and EV71\",\n      \"pmids\": [\n        \"26962226\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether viral suppression is a direct consequence of Golgi/trafficking disruption versus another pathway is not formally separated\",\n        \"No direct interaction between BPIFB6 and viral proteins demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of BPIFB6 \\u2014 whether it binds lipids or LPS as its family suggests, and how an ER protein controls Golgi morphology and trafficking \\u2014 remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct lipid/LPS binding assay reported\",\n        \"No structural model or substrate identified\",\n        \"Mechanism coupling ER residence to Golgi integrity unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005783\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-9609507\",\n        \"supporting_discovery_ids\": [\n          3\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-5653656\",\n        \"supporting_discovery_ids\": [\n          3\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}