{"gene":"HDLBP","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2022,"finding":"HDLBP directly interacts with more than 80% of ER-localized mRNAs, binding specifically in their coding sequences (CDS) via long CU-rich motifs through multivalent interactions, and its absence results in decreased translation efficiency of target mRNAs and impaired protein synthesis and secretion.","method":"PAR-CLIP analysis, quantification of HDLBP-proximal proteome, loss-of-function experiments in model cell lines measuring translation efficiency and secretion","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (PAR-CLIP, proximity proteomics, KO phenotype with translation efficiency quantification) in a single rigorous study","pmids":["35585045"],"is_preprint":false},{"year":2022,"finding":"HDLBP binds to and stabilizes the long noncoding RNA lncFAL (derived from the plexin B2 gene), and this stabilization reduces ferroptosis vulnerability in HCC by allowing lncFAL to competitively inhibit Trim69-dependent FSP1 polyubiquitination and degradation.","method":"RNA immunoprecipitation, co-immunoprecipitation, in vitro and in vivo functional assays measuring ferroptosis vulnerability and FSP1 protein stability","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and ubiquitination assays in a single lab with multiple orthogonal methods","pmids":["36423520"],"is_preprint":false},{"year":2022,"finding":"HDLBP interacts with BRAF protein and inhibits its ubiquitin-proteasome degradation by competing with the ITCH E3 ligase, thereby promoting EMT signaling in HCC cells.","method":"Co-immunoprecipitation, mass spectrometry screening, ubiquitination assay, knockdown/overexpression in vitro and in vivo","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mass spectrometry identification, ubiquitination assays, single lab with multiple methods","pmids":["36122630"],"is_preprint":false},{"year":2022,"finding":"HDLBP interacts with RAF1 protein and inhibits its ubiquitin-proteasome degradation by competing with the TRIM71 E3 ligase, thereby sustaining MEKK1-induced RAF1-Ser259-dependent MAPK signaling and promoting HCC proliferation and sorafenib resistance.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, knockdown/overexpression experiments in vitro and in vivo","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mass spectrometry, ubiquitination assays, single lab with multiple orthogonal methods","pmids":["36244648"],"is_preprint":false},{"year":2021,"finding":"TSC2 protein physically binds to HDLBP/vigilin, a core stress granule (SG) protein, and TSC2 localizes to stress granules; knockdown of vigilin/HDLBP impacts TSC2 stress granule translocation.","method":"Co-immunoprecipitation, immunofluorescence localization, knockdown experiments with stress granule quantification","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and localization imaging with functional KD, single lab","pmids":["33888601"],"is_preprint":false},{"year":2025,"finding":"HDLBP-dependent transmembrane protein (TMP) synthesis at the axonal ER regulates axonal ERES (ER exit sites) formation, establishing a feedback loop coupling local TMP translation to secretion; HDLBP loss impairs axon growth and bouton assembly.","method":"Live imaging in neurons, genetic loss-of-function (HDLBP depletion), assessment of ERES formation and axonal growth phenotypes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization and loss-of-function experiments with defined cellular phenotypes, single lab preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.09.674816"],"is_preprint":true},{"year":2025,"finding":"HDLBP stabilizes GJB2 mRNA by binding to it (RNA-binding), enhancing GJB2 expression to promote glycolysis and CD8+ T cell exhaustion in lung adenocarcinoma cells.","method":"RNA immunoprecipitation (RIP), gain/loss-of-function assays measuring glucose uptake, lactate production, and T cell exhaustion in co-culture and mouse allograft models","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirmed direct binding, multiple functional readouts including in vivo, single lab","pmids":["40343852"],"is_preprint":false},{"year":1993,"finding":"The HDLBP gene was localized to human chromosome 2q37 by somatic cell hybrid analysis and in situ hybridization; the encoded protein was identified as a 110-kDa protein that specifically binds HDL molecules.","method":"Somatic cell hybrid analysis, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytogenetic mapping with two orthogonal methods, foundational characterization","pmids":["8390966"],"is_preprint":false}],"current_model":"HDLBP (Vigilin) is a large, multi-KH-domain RNA-binding protein that localizes primarily to the cytoplasmic face of the endoplasmic reticulum, where it binds CU-rich motifs in the coding sequences of ER-targeted mRNAs via multivalent interactions to promote their translation and secretion; it also stabilizes specific mRNAs (e.g., GJB2) in the cytosol, physically interacts with and protects signaling proteins (BRAF, RAF1) from ubiquitin-proteasome degradation by competing with E3 ligases (ITCH, TRIM71), binds the lncRNA lncFAL to suppress ferroptosis, physically associates with the TSC2 tumor suppressor at stress granules, and couples axonal transmembrane protein synthesis to ER exit site formation during neuronal development."},"narrative":{"mechanistic_narrative":"HDLBP (Vigilin) is a multivalent RNA-binding protein that couples mRNA fate to protein synthesis and secretion at the endoplasmic reticulum [PMID:35585045]. It binds long CU-rich motifs in the coding sequences of the majority of ER-localized mRNAs, and its loss decreases their translation efficiency and impairs protein synthesis and secretion [PMID:35585045]; in neurons, HDLBP-dependent transmembrane protein synthesis at the axonal ER feeds back to drive ER exit site formation and supports axon growth and bouton assembly [PMID:bio_10.1101_2025.09.09.674816]. Beyond ER-coupled translation, HDLBP stabilizes specific transcripts in trans, binding and stabilizing GJB2 mRNA to promote glycolysis [PMID:40343852] and binding the lncRNA lncFAL to suppress ferroptosis through competitive inhibition of TRIM69-dependent FSP1 polyubiquitination [PMID:36423520]. HDLBP also acts as a protein stabilizer in oncogenic signaling, binding BRAF and RAF1 and shielding them from ubiquitin-proteasome degradation by competing with the E3 ligases ITCH and TRIM71, respectively, thereby sustaining MAPK/EMT signaling [PMID:36122630, PMID:36244648]. It additionally associates with the TSC2 tumor suppressor and influences TSC2 recruitment to stress granules [PMID:33888601]. The protein was originally identified as a 110-kDa HDL-binding protein encoded at chromosome 2q37 [PMID:8390966].","teleology":[{"year":1993,"claim":"Before molecular characterization, the gene's identity and product were unknown; mapping and biochemical identification established HDLBP as a defined 110-kDa locus, anchoring all subsequent work.","evidence":"Somatic cell hybrid analysis and FISH mapping with biochemical identification of an HDL-binding protein","pmids":["8390966"],"confidence":"Medium","gaps":["The reported HDL-binding activity is not connected to any later RNA-binding mechanism","No domain or functional model established at this stage"]},{"year":2021,"claim":"To understand HDLBP's role in stress responses, its protein partners were probed, showing it associates with TSC2 and influences TSC2 stress granule localization, placing HDLBP in the stress granule compartment.","evidence":"Reciprocal Co-IP, immunofluorescence localization, and knockdown with stress granule quantification","pmids":["33888601"],"confidence":"Medium","gaps":["Direct binding interface and stoichiometry with TSC2 not defined","Functional consequence of TSC2 mislocalization for mTOR signaling not resolved"]},{"year":2022,"claim":"The central question of how HDLBP controls gene expression was answered by transcriptome-wide mapping showing it binds CU-rich CDS motifs of most ER mRNAs and is required for their efficient translation and secretion, defining HDLBP as an ER-coupled translational regulator.","evidence":"PAR-CLIP, proximity proteomics, and loss-of-function translation/secretion assays in cell lines","pmids":["35585045"],"confidence":"High","gaps":["Mechanism by which CDS binding enhances translation efficiency is not resolved","Whether multivalent KH-domain engagement directly recruits the translation machinery is untested"]},{"year":2022,"claim":"Parallel cancer studies revealed a distinct, post-translational role: HDLBP binds BRAF and RAF1 and protects them from degradation by competing with specific E3 ligases, linking HDLBP to MAPK/EMT signaling and therapy resistance.","evidence":"Co-IP with mass spectrometry, ubiquitination assays, and knockdown/overexpression in vitro and in vivo","pmids":["36122630","36244648"],"confidence":"Medium","gaps":["Whether HDLBP binds RAF kinases directly or via an adaptor is not established","Structural basis for E3 ligase competition unknown","Relationship between RNA-binding and protein-stabilizing functions unclear"]},{"year":2022,"claim":"An RNA-based mechanism in redox biology was uncovered: HDLBP binds and stabilizes lncFAL, which competitively blocks TRIM69-dependent FSP1 ubiquitination, establishing HDLBP as a suppressor of ferroptosis.","evidence":"RNA immunoprecipitation, Co-IP, and ferroptosis/FSP1 stability assays in vitro and in vivo","pmids":["36423520"],"confidence":"Medium","gaps":["Binding determinants on lncFAL not mapped","Generality of HDLBP lncRNA stabilization beyond lncFAL untested"]},{"year":2025,"claim":"HDLBP's mRNA-stabilizing activity was extended to immunometabolism, showing it stabilizes GJB2 mRNA to drive glycolysis and CD8+ T cell exhaustion in lung adenocarcinoma.","evidence":"RIP, gain/loss-of-function metabolic readouts, and co-culture and allograft models","pmids":["40343852"],"confidence":"Medium","gaps":["Sequence motif mediating GJB2 mRNA binding not defined","How transcript stabilization mechanistically differs from the CDS-based translational role is unclear"]},{"year":2025,"claim":"The ER-coupled translation role was given a developmental, spatial dimension by showing HDLBP-dependent transmembrane protein synthesis at the axonal ER drives ER exit site formation, establishing a local translation–secretion feedback loop required for axon growth.","evidence":"Live imaging in neurons with genetic loss-of-function and ERES/axon growth phenotyping (preprint)","pmids":["bio_10.1101_2025.09.09.674816"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Molecular link between local translation and ERES biogenesis not defined"]},{"year":null,"claim":"It remains unresolved how HDLBP's multiple activities — ER-coupled CDS-directed translation, cytosolic mRNA/lncRNA stabilization, and protein stabilization via E3 ligase competition — are integrated within a single protein and partitioned across subcellular compartments.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking KH-domain RNA binding to protein-protein stabilization","Determinants directing HDLBP between ER, cytosol, and stress granules unknown","No mechanistic account unifying RNA-binding and ubiquitination-competition functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]}],"complexes":["stress granule"],"partners":["BRAF","RAF1","TSC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q00341","full_name":"Vigilin","aliases":["High density lipoprotein-binding protein","HDL-binding protein"],"length_aa":1268,"mass_kda":141.4,"function":"Appears to play a role in cell sterol metabolism. It may function to protect cells from over-accumulation of cholesterol","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q00341/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDLBP","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATG13","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HDLBP","total_profiled":1310},"omim":[{"mim_id":"142695","title":"HIGH DENSITY LIPOPROTEIN-BINDING PROTEIN; HDLBP","url":"https://www.omim.org/entry/142695"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDLBP"},"hgnc":{"alias_symbol":["HBP"],"prev_symbol":["VGL"]},"alphafold":{"accession":"Q00341","domains":[{"cath_id":"3.30.1370.10","chopping":"77-88_99-218","consensus_level":"medium","plddt":81.7298,"start":77,"end":218},{"cath_id":"3.30.1370.10","chopping":"364-435","consensus_level":"medium","plddt":80.0989,"start":364,"end":435},{"cath_id":"3.30.1370.10","chopping":"436-505","consensus_level":"medium","plddt":80.694,"start":436,"end":505},{"cath_id":"3.30.1370.10","chopping":"515-579","consensus_level":"medium","plddt":79.6592,"start":515,"end":579},{"cath_id":"3.30.1370.10","chopping":"583-645","consensus_level":"high","plddt":78.7321,"start":583,"end":645},{"cath_id":"3.30.1370.10","chopping":"668-723","consensus_level":"medium","plddt":75.1236,"start":668,"end":723},{"cath_id":"3.30.1370.10","chopping":"974-1052","consensus_level":"medium","plddt":84.4997,"start":974,"end":1052}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00341","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00341-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00341-F1-predicted_aligned_error_v6.png","plddt_mean":74.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDLBP","jax_strain_url":"https://www.jax.org/strain/search?query=HDLBP"},"sequence":{"accession":"Q00341","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00341.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00341/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00341"}},"corpus_meta":[{"pmid":"15467096","id":"PMC_15467096","title":"The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis.","date":"2004","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/15467096","citation_count":330,"is_preprint":false},{"pmid":"36423520","id":"PMC_36423520","title":"HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/36423520","citation_count":81,"is_preprint":false},{"pmid":"15287000","id":"PMC_15287000","title":"Transcription cofactor Vgl-2 is required for skeletal muscle differentiation.","date":"2004","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/15287000","citation_count":53,"is_preprint":false},{"pmid":"19365831","id":"PMC_19365831","title":"FARP2, HDLBP and PASK are downregulated in a patient with autism and 2q37.3 deletion syndrome.","date":"2009","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/19365831","citation_count":34,"is_preprint":false},{"pmid":"36122630","id":"PMC_36122630","title":"The lipid transporter HDLBP promotes hepatocellular carcinoma metastasis through BRAF-dependent epithelial-mesenchymal transition.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/36122630","citation_count":23,"is_preprint":false},{"pmid":"21839727","id":"PMC_21839727","title":"A novel inhibitor of apoptosis protein (IAP)-interacting protein, Vestigial-like (Vgl)-4, counteracts apoptosis-inhibitory function of IAPs by nuclear sequestration.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21839727","citation_count":23,"is_preprint":false},{"pmid":"35585045","id":"PMC_35585045","title":"HDLBP binds ER-targeted mRNAs by multivalent interactions to promote protein synthesis of transmembrane and secreted proteins.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35585045","citation_count":21,"is_preprint":false},{"pmid":"36244648","id":"PMC_36244648","title":"HDLBP Promotes Hepatocellular Carcinoma Proliferation and Sorafenib Resistance by Suppressing Trim71-dependent RAF1 Degradation.","date":"2022","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/36244648","citation_count":20,"is_preprint":false},{"pmid":"33888601","id":"PMC_33888601","title":"TSC2 Interacts with HDLBP/Vigilin and Regulates Stress Granule Formation.","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/33888601","citation_count":18,"is_preprint":false},{"pmid":"8390966","id":"PMC_8390966","title":"Localization of the gene for high-density lipoprotein binding protein (HDLBP) to human chromosome 2q37.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8390966","citation_count":12,"is_preprint":false},{"pmid":"38477883","id":"PMC_38477883","title":"The high-density lipoprotein binding protein HDLBP is an unusual RNA-binding protein with multiple roles in cancer and disease.","date":"2024","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/38477883","citation_count":10,"is_preprint":false},{"pmid":"40343852","id":"PMC_40343852","title":"HDLBP Promotes Glycolysis and CD8+ T Cell Exhaustion in Lung Adenocarcinoma by Stabilizing GJB2 RNA.","date":"2025","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40343852","citation_count":4,"is_preprint":false},{"pmid":"41828375","id":"PMC_41828375","title":"Phosphoproteomic Landscape of HDLBP: Insights into Function and Disease Associations.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41828375","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.09.674816","title":"The axonal ER couples translation and secretion machineries for local delivery of axonal transmembrane proteins to promote axonal development","date":"2025-09-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.674816","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.10.630794","title":"Database Permeating through Time, Space, and Medicine: A sequence, structure, and clinical compilation and comparison of transmembrane amino acids in VGL ion channels","date":"2025-01-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.630794","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.15.638427","title":"Voltage-gated ion channel diversity underlies neuronal excitability and nervous system evolution","date":"2025-02-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.15.638427","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.01.636073","title":"Evaluation of sequencing reads at scale using rdeval","date":"2025-02-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.01.636073","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9665,"output_tokens":1891,"usd":0.02868,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8826,"output_tokens":2959,"usd":0.059053,"stage2_stop_reason":"end_turn"},"total_usd":0.087733,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"HDLBP directly interacts with more than 80% of ER-localized mRNAs, binding specifically in their coding sequences (CDS) via long CU-rich motifs through multivalent interactions, and its absence results in decreased translation efficiency of target mRNAs and impaired protein synthesis and secretion.\",\n      \"method\": \"PAR-CLIP analysis, quantification of HDLBP-proximal proteome, loss-of-function experiments in model cell lines measuring translation efficiency and secretion\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (PAR-CLIP, proximity proteomics, KO phenotype with translation efficiency quantification) in a single rigorous study\",\n      \"pmids\": [\"35585045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDLBP binds to and stabilizes the long noncoding RNA lncFAL (derived from the plexin B2 gene), and this stabilization reduces ferroptosis vulnerability in HCC by allowing lncFAL to competitively inhibit Trim69-dependent FSP1 polyubiquitination and degradation.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, in vitro and in vivo functional assays measuring ferroptosis vulnerability and FSP1 protein stability\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and ubiquitination assays in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36423520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDLBP interacts with BRAF protein and inhibits its ubiquitin-proteasome degradation by competing with the ITCH E3 ligase, thereby promoting EMT signaling in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry screening, ubiquitination assay, knockdown/overexpression in vitro and in vivo\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mass spectrometry identification, ubiquitination assays, single lab with multiple methods\",\n      \"pmids\": [\"36122630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDLBP interacts with RAF1 protein and inhibits its ubiquitin-proteasome degradation by competing with the TRIM71 E3 ligase, thereby sustaining MEKK1-induced RAF1-Ser259-dependent MAPK signaling and promoting HCC proliferation and sorafenib resistance.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, knockdown/overexpression experiments in vitro and in vivo\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mass spectrometry, ubiquitination assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36244648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TSC2 protein physically binds to HDLBP/vigilin, a core stress granule (SG) protein, and TSC2 localizes to stress granules; knockdown of vigilin/HDLBP impacts TSC2 stress granule translocation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, knockdown experiments with stress granule quantification\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and localization imaging with functional KD, single lab\",\n      \"pmids\": [\"33888601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDLBP-dependent transmembrane protein (TMP) synthesis at the axonal ER regulates axonal ERES (ER exit sites) formation, establishing a feedback loop coupling local TMP translation to secretion; HDLBP loss impairs axon growth and bouton assembly.\",\n      \"method\": \"Live imaging in neurons, genetic loss-of-function (HDLBP depletion), assessment of ERES formation and axonal growth phenotypes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization and loss-of-function experiments with defined cellular phenotypes, single lab preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.674816\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDLBP stabilizes GJB2 mRNA by binding to it (RNA-binding), enhancing GJB2 expression to promote glycolysis and CD8+ T cell exhaustion in lung adenocarcinoma cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), gain/loss-of-function assays measuring glucose uptake, lactate production, and T cell exhaustion in co-culture and mouse allograft models\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirmed direct binding, multiple functional readouts including in vivo, single lab\",\n      \"pmids\": [\"40343852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The HDLBP gene was localized to human chromosome 2q37 by somatic cell hybrid analysis and in situ hybridization; the encoded protein was identified as a 110-kDa protein that specifically binds HDL molecules.\",\n      \"method\": \"Somatic cell hybrid analysis, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytogenetic mapping with two orthogonal methods, foundational characterization\",\n      \"pmids\": [\"8390966\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDLBP (Vigilin) is a large, multi-KH-domain RNA-binding protein that localizes primarily to the cytoplasmic face of the endoplasmic reticulum, where it binds CU-rich motifs in the coding sequences of ER-targeted mRNAs via multivalent interactions to promote their translation and secretion; it also stabilizes specific mRNAs (e.g., GJB2) in the cytosol, physically interacts with and protects signaling proteins (BRAF, RAF1) from ubiquitin-proteasome degradation by competing with E3 ligases (ITCH, TRIM71), binds the lncRNA lncFAL to suppress ferroptosis, physically associates with the TSC2 tumor suppressor at stress granules, and couples axonal transmembrane protein synthesis to ER exit site formation during neuronal development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDLBP (Vigilin) is a multivalent RNA-binding protein that couples mRNA fate to protein synthesis and secretion at the endoplasmic reticulum [#0]. It binds long CU-rich motifs in the coding sequences of the majority of ER-localized mRNAs, and its loss decreases their translation efficiency and impairs protein synthesis and secretion [#0]; in neurons, HDLBP-dependent transmembrane protein synthesis at the axonal ER feeds back to drive ER exit site formation and supports axon growth and bouton assembly [#5]. Beyond ER-coupled translation, HDLBP stabilizes specific transcripts in trans, binding and stabilizing GJB2 mRNA to promote glycolysis [#6] and binding the lncRNA lncFAL to suppress ferroptosis through competitive inhibition of TRIM69-dependent FSP1 polyubiquitination [#1]. HDLBP also acts as a protein stabilizer in oncogenic signaling, binding BRAF and RAF1 and shielding them from ubiquitin-proteasome degradation by competing with the E3 ligases ITCH and TRIM71, respectively, thereby sustaining MAPK/EMT signaling [#2, #3]. It additionally associates with the TSC2 tumor suppressor and influences TSC2 recruitment to stress granules [#4]. The protein was originally identified as a 110-kDa HDL-binding protein encoded at chromosome 2q37 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Before molecular characterization, the gene's identity and product were unknown; mapping and biochemical identification established HDLBP as a defined 110-kDa locus, anchoring all subsequent work.\",\n      \"evidence\": \"Somatic cell hybrid analysis and FISH mapping with biochemical identification of an HDL-binding protein\",\n      \"pmids\": [\"8390966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The reported HDL-binding activity is not connected to any later RNA-binding mechanism\",\n        \"No domain or functional model established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To understand HDLBP's role in stress responses, its protein partners were probed, showing it associates with TSC2 and influences TSC2 stress granule localization, placing HDLBP in the stress granule compartment.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence localization, and knockdown with stress granule quantification\",\n      \"pmids\": [\"33888601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface and stoichiometry with TSC2 not defined\",\n        \"Functional consequence of TSC2 mislocalization for mTOR signaling not resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The central question of how HDLBP controls gene expression was answered by transcriptome-wide mapping showing it binds CU-rich CDS motifs of most ER mRNAs and is required for their efficient translation and secretion, defining HDLBP as an ER-coupled translational regulator.\",\n      \"evidence\": \"PAR-CLIP, proximity proteomics, and loss-of-function translation/secretion assays in cell lines\",\n      \"pmids\": [\"35585045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CDS binding enhances translation efficiency is not resolved\",\n        \"Whether multivalent KH-domain engagement directly recruits the translation machinery is untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Parallel cancer studies revealed a distinct, post-translational role: HDLBP binds BRAF and RAF1 and protects them from degradation by competing with specific E3 ligases, linking HDLBP to MAPK/EMT signaling and therapy resistance.\",\n      \"evidence\": \"Co-IP with mass spectrometry, ubiquitination assays, and knockdown/overexpression in vitro and in vivo\",\n      \"pmids\": [\"36122630\", \"36244648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether HDLBP binds RAF kinases directly or via an adaptor is not established\",\n        \"Structural basis for E3 ligase competition unknown\",\n        \"Relationship between RNA-binding and protein-stabilizing functions unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An RNA-based mechanism in redox biology was uncovered: HDLBP binds and stabilizes lncFAL, which competitively blocks TRIM69-dependent FSP1 ubiquitination, establishing HDLBP as a suppressor of ferroptosis.\",\n      \"evidence\": \"RNA immunoprecipitation, Co-IP, and ferroptosis/FSP1 stability assays in vitro and in vivo\",\n      \"pmids\": [\"36423520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding determinants on lncFAL not mapped\",\n        \"Generality of HDLBP lncRNA stabilization beyond lncFAL untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"HDLBP's mRNA-stabilizing activity was extended to immunometabolism, showing it stabilizes GJB2 mRNA to drive glycolysis and CD8+ T cell exhaustion in lung adenocarcinoma.\",\n      \"evidence\": \"RIP, gain/loss-of-function metabolic readouts, and co-culture and allograft models\",\n      \"pmids\": [\"40343852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Sequence motif mediating GJB2 mRNA binding not defined\",\n        \"How transcript stabilization mechanistically differs from the CDS-based translational role is unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The ER-coupled translation role was given a developmental, spatial dimension by showing HDLBP-dependent transmembrane protein synthesis at the axonal ER drives ER exit site formation, establishing a local translation–secretion feedback loop required for axon growth.\",\n      \"evidence\": \"Live imaging in neurons with genetic loss-of-function and ERES/axon growth phenotyping (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.674816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Molecular link between local translation and ERES biogenesis not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how HDLBP's multiple activities — ER-coupled CDS-directed translation, cytosolic mRNA/lncRNA stabilization, and protein stabilization via E3 ligase competition — are integrated within a single protein and partitioned across subcellular compartments.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model linking KH-domain RNA binding to protein-protein stabilization\",\n        \"Determinants directing HDLBP between ER, cytosol, and stress granules unknown\",\n        \"No mechanistic account unifying RNA-binding and ubiquitination-competition functions\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"stress granule\"],\n    \"partners\": [\"BRAF\", \"RAF1\", \"TSC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}