{"gene":"HNRNPAB","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2012,"finding":"hnRNP A/B knockdown in primary neurons induced alternative splicing impairments and dendrite loss, and caused memory and electrocorticographic impairments in mice; cholinergic excitation increased hnRNP A/B levels while neurotoxin-mediated destruction of cholinergic neurons caused cortical decrease in hnRNP A/B and recapitulated AD-like alternative splicing patterns, establishing cholinergic regulation of hnRNP A/B as a mechanism controlling cortical splicing.","method":"hnRNP A/B knockdown in primary neurons and mice, in vivo cholinergic neurotoxin lesion, electrocorticography, behavioral memory testing","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with defined cellular and behavioral phenotype, multiple readouts in single lab","pmids":["22628224"],"is_preprint":false},{"year":2004,"finding":"Drosophila hnRNP A/B homolog Hrp48 (ortholog of HNRNPAB) binds to the 5' and 3' regions of oskar mRNA and is required for translational repression of unlocalized oskar mRNA during transport; Hrp48 levels are crucial for polarization of the oocyte during mid-oogenesis.","method":"Genetic mutant analysis (three hrp48 alleles), RNA binding assays, oocyte phenotypic analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent papers using genetic alleles, RNA binding, and functional readouts, replicated across labs","pmids":["15130489","15130488"],"is_preprint":false},{"year":2004,"finding":"Drosophila Hrp48 colocalizes with oskar mRNA throughout oogenesis and its loss specifically abolishes oskar mRNA posterior localization without affecting translational control, splicing, or other mRNA localizations; Hrp48 mutations disrupt GFP-Staufen particle formation, defining a new step in the localization pathway.","method":"Germline clone screen, live imaging of GFP-Staufen, genetic mutant analysis (three missense alleles), RNA localization assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent concurrent papers using genetic alleles and imaging with orthogonal readouts","pmids":["15130488","15130489"],"is_preprint":false},{"year":2013,"finding":"CBF-A/Hnrnpab directly binds the A2RE/RTS element in the 3' UTR of Protamine2 (Prm2) mRNA and contributes to temporal translational regulation during spermatogenesis; the p42 isoform associates with translationally active (de-repressed) Prm2 mRNA and interacts with the 5' cap complex and polysomes, whereas p37 associates with translationally repressed Prm2 mRNA; Hnrnpab knockout mice show reduced PRM2 expression and premature Prm2 translation with abnormal sperm DNA morphology.","method":"RNA immunoprecipitation, direct binding assay, polysome fractionation, 5' cap complex pulldown, Hnrnpab knockout mouse analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (direct binding, polysome fractionation, cap-complex interaction, KO mouse) in single study","pmids":["24146628"],"is_preprint":false},{"year":2014,"finding":"HNRNPAB transcriptionally activates SNAIL1, which in turn represses E-cadherin transcription, thereby promoting epithelial-mesenchymal transition (EMT) and metastasis of hepatocellular carcinoma; siRNA-mediated silencing of SNAIL attenuated HNRNPAB-enhanced invasion in vitro and lung metastasis in vivo.","method":"RNA interference (siRNA), overexpression, in vitro invasion assays, in vivo lung metastasis model, reporter and ChIP assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via SNAIL knockdown rescue, in vivo metastasis model, single lab with multiple orthogonal methods","pmids":["24638979"],"is_preprint":false},{"year":2012,"finding":"Hnrnpab knockout mouse neural stem and progenitor cells undergo altered differentiation patterns; mature Hnrnpab(-/-) neurons show increased sensitivity to glutamate-induced excitotoxicity; Hnrnpab nucleocytoplasmic distribution in primary neurons is regulated by developmental stage.","method":"Hnrnpab knockout mouse, neural stem cell culture, glutamate excitotoxicity assay, subcellular fractionation/localization","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotypes and localization experiment, single lab","pmids":["22332140"],"is_preprint":false},{"year":2018,"finding":"Hnrnpab regulates transcription of Eps8 in the subventricular zone; loss of Hnrnpab decreases Eps8 expression and impairs neural cell migration from the SVZ; both alternatively spliced Hnrnpab isoforms (p37 and p42) are required together (non-redundantly) to restore Eps8 transcription and cell motility.","method":"Hnrnpab knockout mouse, SVZ migration assay, RNA-seq, ectopic re-expression of individual isoforms","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined migration phenotype, RNA-seq, rescue by isoform re-expression, single lab","pmids":["30314980"],"is_preprint":false},{"year":2021,"finding":"hnRNPAB interacts with influenza A virus nucleoprotein (NP) and restricts viral mRNA nuclear export by inhibiting mRNA transfer from ALY to NXF1; NP cooperates with hnRNPAB to interrupt the ALY-UAP56 interaction, repressing ALY-viral mRNA binding and nuclear export of viral mRNA.","method":"Co-immunoprecipitation, overexpression/knockdown, nuclear export assays, binding competition assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional export assays, single lab with multiple readouts","pmids":["33681726"],"is_preprint":false},{"year":2024,"finding":"hnRNPAB interacts with influenza A virus NP via a 5-amino-acid peptide at its C-terminal domain (aa 318-322) to inhibit the PB1-NP interaction, thereby disrupting FluPol complex assembly and inhibiting viral polymerase activity; hnRNPAB-deficient mice show higher viral burdens and increased mortality after influenza infection.","method":"Co-immunoprecipitation, domain mapping (5-aa peptide), viral polymerase activity assay, hnRNPAB knockout mouse in vivo infection","journal":"Antiviral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-level mapping of interaction interface, in vitro polymerase assay, and in vivo KO mouse validation across orthogonal methods","pmids":["38944160"],"is_preprint":false},{"year":2021,"finding":"hnRNPAB associates with avian influenza viral PB2 mRNA; overexpression of hnRNPAB reduces PB2 mRNA nuclear export and PB2 protein level (without changing PB2 mRNA level), restricts viral polymerase activity, and inhibits virus replication; virus infection induces nuclear accumulation of hnRNPAB.","method":"RNA immunoprecipitation, overexpression/knockdown, mRNA nuclear export assay, viral polymerase activity assay, subcellular fractionation","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP, nuclear export assay, polymerase activity, and localization experiments, single lab","pmids":["34555436"],"is_preprint":false},{"year":2021,"finding":"lnc-CTSLP4 binds HNRNPAB within an Hsp90α/HNRNPAB complex and recruits E3-ubiquitin ligase ZFP91 to induce ubiquitination and degradation of HNRNPAB, thereby suppressing HNRNPAB-dependent transcriptional activation of Snail and reversing EMT in gastric cancer cells.","method":"RNA pull-down, co-immunoprecipitation, ubiquitination assay, gain/loss-of-function assays, peritoneal dissemination in vivo model","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown, Co-IP, ubiquitination assay with defined E3 ligase, single lab","pmids":["33717650"],"is_preprint":false},{"year":2025,"finding":"tRF-22 binds to Lys91 on hnRNPAB and inhibits its ubiquitination by TRIM25, leading to hnRNPAB stabilization; stabilized hnRNPAB activates TGFB2 transcription, which promotes PMN-MDSC generation and immunosuppression in esophageal squamous cell carcinoma.","method":"RNA-protein binding assay (residue-level), ubiquitination assay, TRIM25 identification, TGFB2 transcription reporter/ChIP, immune cell infiltration analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-level binding (Lys91), ubiquitination by specific E3, transcriptional activation assay, single lab","pmids":["41144758"],"is_preprint":false},{"year":2024,"finding":"hnRNPAB binds MYC mRNA and prolongs its half-life (mRNA stabilization), thereby increasing MYC protein levels and downstream CXCL8 secretion, which promotes neutrophil recruitment and facilitates liver metastasis in pancreatic ductal adenocarcinoma.","method":"RNA immunoprecipitation, mRNA stability assay (half-life measurement), xenograft metastasis model, CXCL8 secretion assay","journal":"Molecular cancer research: MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, mRNA half-life assay, in vivo metastasis model, single lab","pmids":["38967522"],"is_preprint":false},{"year":2023,"finding":"hnRNPAB is a direct transcriptional target of c-Myc (ChIP and luciferase reporter confirmed); hnRNPAB binds CDK4 mRNA and stabilizes it, increasing CDK4 protein levels and promoting G1/S cell cycle progression and lung adenocarcinoma cell proliferation; hnRNPAB mediates the proliferative effect of c-Myc.","method":"ChIP, luciferase reporter assay, RNA immunoprecipitation (RIP), flow cytometry, colony formation assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, luciferase reporter, RIP with functional cell cycle readout, single lab","pmids":["36657708"],"is_preprint":false},{"year":2019,"finding":"HNRNPAB represses transcription of lnc-ELF209 by directly binding to its promoter region, as demonstrated by chromatin immunoprecipitation; lnc-ELF209 in turn inhibits HNRNPAB-promoted HCC cell migration, invasion, and EMT.","method":"Chromatin immunoprecipitation (ChIP), lncRNA microarray, qRT-PCR, gain/loss-of-function assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, functional rescue assays, single lab","pmids":["31090062"],"is_preprint":false},{"year":2025,"finding":"lncRNA Ntoco binds Hnrnpab and facilitates K48-linked ubiquitination and degradation of Hnrnpab, suppressing NF-κB/Lcn2 signaling (reduced IkBα phosphorylation, increased IKKα/β phosphorylation, nuclear translocation of NF-κB p65, elevated Lcn2), thereby promoting ferroptosis in neurons following traumatic brain injury.","method":"RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay (K48 linkage), western blotting, in vivo CCI mouse model","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown, RIP, K48 ubiquitination, pathway signaling assays, in vivo model, single lab","pmids":["39976282"],"is_preprint":false},{"year":2025,"finding":"KAP1 interacts with HNRNPAB as identified by mass spectrometry, further modulating YAP1 signaling in gastric adenocarcinoma.","method":"Mass spectrometry (protein interaction), co-immunoprecipitation implied","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single MS identification of interaction, limited functional follow-up on HNRNPAB specifically","pmids":["40189014"],"is_preprint":false},{"year":2026,"finding":"HNRNPAB promotes back-splicing and expression of circESR1 by binding to Alu elements of cognate ESR1 pre-mRNA; HNRNPAB also binds and stabilizes CDK1 and CDK6 mRNAs, and this stabilization is facilitated by asymmetrical circESR1 binding to HNRNPAB, promoting cell cycle progression in ER+ breast cancer cells.","method":"RNA immunoprecipitation, mRNA stability assay, overexpression/knockdown, flow cytometry for cell cycle","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, stability assay, functional cell cycle readouts; single lab but multiple orthogonal methods","pmids":["41608617"],"is_preprint":false},{"year":2024,"finding":"tRFValCAC (a sperm-enriched tRNA fragment) interacts with hnRNPAB in the epididymis, and this interaction regulates sorting and packing of tRFValCAC into extracellular vesicles for delivery to sperm.","method":"RNA-protein interaction assay (RNA pull-down/RIP), extracellular vesicle isolation and characterization","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method RNA-protein interaction, preprint, single lab","pmids":[],"is_preprint":true},{"year":2026,"finding":"Overexpression of duck HNRNPAB reduced MAVS-induced IFNβ promoter activity and MAVS protein abundance, identifying HNRNPAB as a negative regulator of MAVS-mediated Type I IFN signaling.","method":"Overexpression functional assay, IFNβ promoter reporter assay, western blotting for MAVS abundance","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with reporter assay, no endogenous KO/KD validation, single lab","pmids":["41807513"],"is_preprint":false}],"current_model":"HNRNPAB is a multifunctional RNA-binding protein that acts post-transcriptionally (binding 3' UTR elements to regulate mRNA translation, stability, and nuclear export) and transcriptionally (binding gene promoters to activate or repress transcription of targets such as SNAIL1, TGFB2, and lnc-ELF209); its activity is regulated by isoform-specific differences (p37 vs. p42), post-translational modifications including ubiquitination (by TRIM25 and ZFP91), and nucleocytoplasmic redistribution; it plays defined roles in spermatogenesis (temporal Prm2 mRNA translation), neural development and migration (via Eps8 transcription), cholinergic-regulated alternative splicing in the cortex, cancer EMT/metastasis (through SNAIL and MYC mRNA stabilization), and antiviral defense (inhibiting influenza polymerase complex assembly via NP interaction and restricting viral mRNA nuclear export)."},"narrative":{"mechanistic_narrative":"HNRNPAB is a multifunctional RNA-binding protein that acts at multiple post-transcriptional steps—translational repression, mRNA stabilization, and nuclear export—and additionally functions at the transcriptional level by binding gene promoters [PMID:15130489, PMID:15130488, PMID:24146628, PMID:24638979]. Its ancestral RNA-handling role is captured by the Drosophila ortholog Hrp48, which binds the 5' and 3' regions of oskar mRNA to enforce translational repression during transport and is independently required for posterior oskar localization via Staufen particle assembly [PMID:15130489, PMID:15130488]. In mammals, HNRNPAB directly binds the A2RE/RTS element in the Prm2 3' UTR to impose temporal translational control during spermatogenesis, with isoform partitioning—the p42 isoform associating with translationally active, cap- and polysome-bound Prm2 mRNA and p37 with the repressed pool—such that knockout mice show premature Prm2 translation and abnormal sperm DNA morphology [PMID:24146628]. In the nervous system, HNRNPAB controls cortical alternative splicing under cholinergic regulation, governs neural stem cell differentiation, and transcriptionally drives Eps8 to enable neuronal migration from the subventricular zone, a function requiring both p37 and p42 non-redundantly [PMID:22628224, PMID:22332140, PMID:30314980]. In cancer, HNRNPAB promotes EMT and metastasis by transcriptionally activating SNAIL1 (repressing E-cadherin) and by binding and stabilizing oncogenic transcripts including MYC, CDK4, CDK1/CDK6, driving proliferation and metastatic phenotypes [PMID:24638979, PMID:38967522, PMID:36657708, PMID:41608617]; its abundance is set by ubiquitin-dependent degradation through the E3 ligases ZFP91 and TRIM25, modulated by competing lncRNAs and tRNA-derived fragments that bind HNRNPAB to either promote or block ubiquitination [PMID:33717650, PMID:41144758, PMID:39976282]. In antiviral defense, HNRNPAB binds influenza nucleoprotein via a five-residue C-terminal peptide to block the PB1-NP interaction and FluPol assembly, and restricts viral mRNA nuclear export by interfering with the ALY-NXF1 transfer step, with knockout mice showing higher viral burden and mortality [PMID:33681726, PMID:38944160, PMID:34555436].","teleology":[{"year":2004,"claim":"Established the ancestral function of this protein family in mRNA handling by showing the ortholog both represses translation of unlocalized mRNA and is independently required for its localization.","evidence":"Drosophila hrp48 genetic alleles, RNA binding assays, and live imaging of GFP-Staufen during oogenesis","pmids":["15130489","15130488"],"confidence":"High","gaps":["Drosophila ortholog—does not establish human HNRNPAB binding sites or partners","Translational repression and localization shown to be separable activities, but molecular basis of each not resolved"]},{"year":2012,"claim":"Defined HNRNPAB as a regulator of cortical alternative splicing under upstream cholinergic control and linked its loss to dendritic and memory deficits, connecting the protein to neurodegeneration-relevant splicing.","evidence":"hnRNP A/B knockdown in primary neurons and mice, cholinergic neurotoxin lesion, electrocorticography, behavioral testing","pmids":["22628224"],"confidence":"Medium","gaps":["Specific spliced target transcripts not enumerated","Mechanism linking cholinergic signaling to hnRNP A/B level not defined"]},{"year":2012,"claim":"Showed HNRNPAB controls neural stem cell differentiation and neuronal excitotoxicity sensitivity, and that its nucleocytoplasmic distribution is developmentally regulated.","evidence":"Hnrnpab knockout mouse, neural stem cell culture, glutamate excitotoxicity assay, subcellular fractionation","pmids":["22332140"],"confidence":"Medium","gaps":["Molecular targets mediating differentiation phenotype unknown","Signal controlling nucleocytoplasmic redistribution not identified"]},{"year":2013,"claim":"Resolved how HNRNPAB imposes temporal translational control in spermatogenesis through direct 3' UTR element binding and isoform-specific partitioning between repressed and active mRNA pools.","evidence":"RNA-IP, direct binding to A2RE/RTS element, polysome fractionation, cap-complex pulldown, Hnrnpab knockout mouse","pmids":["24146628"],"confidence":"High","gaps":["Structural basis distinguishing p37 vs p42 association not defined","Whether the same isoform logic applies to other mRNAs unknown"]},{"year":2014,"claim":"Identified a transcriptional (rather than purely post-transcriptional) role: HNRNPAB activates SNAIL1 to repress E-cadherin and drive EMT and metastasis.","evidence":"siRNA, overexpression, invasion assays, in vivo lung metastasis model, reporter and ChIP assays in HCC","pmids":["24638979"],"confidence":"Medium","gaps":["How an RNA-binding protein engages the SNAIL1 promoter mechanistically unclear","Cofactors for transcriptional activation not identified"]},{"year":2018,"claim":"Demonstrated non-redundant cooperation of both isoforms in transcriptional control of Eps8 driving neural migration, extending the transcriptional role to development.","evidence":"Hnrnpab knockout mouse, SVZ migration assay, RNA-seq, isoform re-expression rescue","pmids":["30314980"],"confidence":"Medium","gaps":["Mechanism requiring both isoforms together not explained","Direct promoter occupancy at Eps8 not detailed"]},{"year":2021,"claim":"Established HNRNPAB as an antiviral restriction factor that blocks influenza viral mRNA nuclear export by interrupting the ALY-NXF1 transfer step in cooperation with viral NP.","evidence":"Co-IP, overexpression/knockdown, nuclear export and binding competition assays; separate study with avian PB2 mRNA and RNA-IP","pmids":["33681726","34555436"],"confidence":"Medium","gaps":["Whether restriction reflects host defense or viral hijacking of the protein not fully resolved","Direct vs indirect engagement of export machinery not structurally defined"]},{"year":2021,"claim":"Showed HNRNPAB abundance is set by lncRNA-scaffolded E3 ligase recruitment, defining a degradation mechanism that gates its EMT-driving transcriptional activity.","evidence":"RNA pull-down, Co-IP, ubiquitination assay identifying ZFP91 within an Hsp90α/HNRNPAB complex, peritoneal dissemination model in gastric cancer","pmids":["33717650"],"confidence":"Medium","gaps":["Ubiquitination acceptor residue for ZFP91 not mapped","Generality across tissues unknown"]},{"year":2024,"claim":"Mapped the precise interaction interface (C-terminal aa 318-322) by which HNRNPAB blocks PB1-NP binding and FluPol assembly, and confirmed protective antiviral function in vivo.","evidence":"Co-IP, 5-aa domain mapping, viral polymerase activity assay, hnRNPAB knockout mouse influenza infection","pmids":["38944160"],"confidence":"High","gaps":["Relationship between polymerase-assembly block and mRNA-export block not integrated","Structure of the HNRNPAB-NP interface not solved"]},{"year":2024,"claim":"Extended the oncogenic mechanism to mRNA stabilization, showing HNRNPAB prolongs MYC mRNA half-life to drive CXCL8-dependent neutrophil recruitment and liver metastasis.","evidence":"RNA-IP, mRNA half-life measurement, xenograft metastasis model, CXCL8 secretion assay in PDAC","pmids":["38967522"],"confidence":"Medium","gaps":["RNA element recognized in MYC mRNA not defined","Whether stabilization requires a specific isoform unknown"]},{"year":2023,"claim":"Placed HNRNPAB in a feed-forward proliferative circuit: it is a direct c-Myc transcriptional target that in turn stabilizes CDK4 mRNA to drive G1/S progression.","evidence":"ChIP, luciferase reporter, RIP, flow cytometry, colony formation in lung adenocarcinoma","pmids":["36657708"],"confidence":"Medium","gaps":["Direct CDK4 mRNA binding site not mapped","Isoform dependence not addressed"]},{"year":2025,"claim":"Defined small-RNA control of HNRNPAB stability, with tRF-22 binding Lys91 to block TRIM25-mediated ubiquitination, stabilizing HNRNPAB to activate TGFB2 transcription and immunosuppression.","evidence":"Residue-level RNA-protein binding, ubiquitination assay, TRIM25 identification, TGFB2 reporter/ChIP, immune infiltration analysis in ESCC","pmids":["41144758"],"confidence":"Medium","gaps":["Whether Lys91 is the TRIM25 ubiquitination acceptor or only a regulatory site unclear","Interplay with ZFP91-mediated degradation not addressed"]},{"year":2025,"claim":"Linked HNRNPAB degradation to NF-κB/Lcn2 signaling and neuronal ferroptosis, broadening its regulatory reach beyond cancer.","evidence":"RNA pull-down, RIP, Co-IP, K48 ubiquitination assay, signaling western blots, in vivo controlled cortical impact model","pmids":["39976282"],"confidence":"Medium","gaps":["E3 ligase mediating Ntoco-directed degradation not identified","Direct connection between HNRNPAB and NF-κB pathway components not established"]},{"year":2026,"claim":"Showed HNRNPAB can promote back-splicing of circRNA and couple a circRNA cofactor to mRNA stabilization, integrating circular and linear RNA regulation in cell cycle control.","evidence":"RIP, mRNA stability assay, overexpression/knockdown, flow cytometry in ER+ breast cancer","pmids":["41608617"],"confidence":"Medium","gaps":["Mechanism of Alu-element-directed back-splicing not detailed","Stoichiometry of circESR1-HNRNPAB-CDK mRNA complex not resolved"]},{"year":null,"claim":"How HNRNPAB switches between repressing translation, stabilizing mRNA, controlling nuclear export, and binding promoters—and what determines this functional partitioning across isoforms, modifications, and subcellular compartments—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of HNRNPAB on its RNA or promoter targets","Rules governing p37 vs p42 functional specialization not unified","Mechanism by which an RNA-binding protein engages chromatin/promoters not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,12,13,17]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,6,11,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,9,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,3,12,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,9,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,12,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,6]}],"complexes":[],"partners":["NP","TRIM25","ZFP91","KAP1","HSP90AA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99729","full_name":"Heterogeneous nuclear ribonucleoprotein A/B","aliases":["APOBEC1-binding protein 1","ABBP-1"],"length_aa":332,"mass_kda":36.2,"function":"Binds single-stranded RNA. Has a high affinity for G-rich and U-rich regions of hnRNA. Also binds to APOB mRNA transcripts around the RNA editing site","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99729/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPAB","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":10.0},{"gene":"HNRNPL","stoichiometry":10.0},{"gene":"HNRNPU","stoichiometry":10.0},{"gene":"IGF2BP1","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"HNRNPC","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPAB","total_profiled":1310},"omim":[{"mim_id":"618192","title":"PROSTATE CANCER-ASSOCIATED TRANSCRIPT 19, NONCODING; PCAT19","url":"https://www.omim.org/entry/618192"},{"mim_id":"615492","title":"LONG INTERGENIC NONCODING RNA COX2","url":"https://www.omim.org/entry/615492"},{"mim_id":"611959","title":"PROSTATE CANCER, HEREDITARY, 15; HPC15","url":"https://www.omim.org/entry/611959"},{"mim_id":"608537","title":"VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL","url":"https://www.omim.org/entry/608537"},{"mim_id":"602688","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A/B; HNRNPAB","url":"https://www.omim.org/entry/602688"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HNRNPAB"},"hgnc":{"alias_symbol":["ABBP1","FLJ40338"],"prev_symbol":["HNRPAB"]},"alphafold":{"accession":"Q99729","domains":[{"cath_id":"3.30.70.330","chopping":"58-144","consensus_level":"high","plddt":86.478,"start":58,"end":144},{"cath_id":"3.30.70.330","chopping":"155-237","consensus_level":"high","plddt":78.8649,"start":155,"end":237}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99729","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99729-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99729-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPAB","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPAB"},"sequence":{"accession":"Q99729","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99729.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99729/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99729"}},"corpus_meta":[{"pmid":"22628224","id":"PMC_22628224","title":"Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice.","date":"2012","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22628224","citation_count":139,"is_preprint":false},{"pmid":"15130489","id":"PMC_15130489","title":"Hrp48, a Drosophila hnRNPA/B homolog, binds and regulates translation of oskar mRNA.","date":"2004","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/15130489","citation_count":101,"is_preprint":false},{"pmid":"24638979","id":"PMC_24638979","title":"HNRNPAB induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24638979","citation_count":96,"is_preprint":false},{"pmid":"15130488","id":"PMC_15130488","title":"The Drosophila hnRNPA/B homolog, Hrp48, is specifically required for a distinct step in osk mRNA localization.","date":"2004","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/15130488","citation_count":88,"is_preprint":false},{"pmid":"33717650","id":"PMC_33717650","title":"Tumor suppressor lnc-CTSLP4 inhibits EMT and metastasis of gastric cancer by attenuating HNRNPAB-dependent Snail transcription.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33717650","citation_count":34,"is_preprint":false},{"pmid":"34291086","id":"PMC_34291086","title":"Post-Translational Modifications Modulate Proteinopathies of TDP-43, FUS and hnRNP-A/B in Amyotrophic Lateral Sclerosis.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34291086","citation_count":32,"is_preprint":false},{"pmid":"24146628","id":"PMC_24146628","title":"The transacting factor CBF-A/Hnrnpab binds to the A2RE/RTS element of protamine 2 mRNA and contributes to its translational regulation during mouse spermatogenesis.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24146628","citation_count":32,"is_preprint":false},{"pmid":"31090062","id":"PMC_31090062","title":"HNRNPAB-regulated lncRNA-ELF209 inhibits the malignancy of hepatocellular carcinoma.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31090062","citation_count":31,"is_preprint":false},{"pmid":"22332140","id":"PMC_22332140","title":"Hnrpab regulates neural development and neuron cell survival after glutamate stimulation.","date":"2012","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22332140","citation_count":24,"is_preprint":false},{"pmid":"33681726","id":"PMC_33681726","title":"Cellular hnRNPAB binding to viral nucleoprotein inhibits flu virus replication by blocking nuclear export of viral mRNA.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/33681726","citation_count":23,"is_preprint":false},{"pmid":"28757026","id":"PMC_28757026","title":"Marek's disease virus type 1 encoded analog of miR-155 promotes proliferation of chicken embryo fibroblast and DF-1 cells by targeting hnRNPAB.","date":"2017","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28757026","citation_count":17,"is_preprint":false},{"pmid":"37165920","id":"PMC_37165920","title":"Knockdown of hnRNPAB reduces the stem cell properties and enhances the chemosensitivity of human colorectal cancer stem cells.","date":"2023","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37165920","citation_count":10,"is_preprint":false},{"pmid":"30314980","id":"PMC_30314980","title":"Hnrnpab regulates neural cell motility through transcription of Eps8.","date":"2018","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30314980","citation_count":8,"is_preprint":false},{"pmid":"38967522","id":"PMC_38967522","title":"hnRNPAB Promotes Pancreatic Ductal Adenocarcinoma Extravasation and Liver Metastasis by Stabilizing MYC mRNA.","date":"2024","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/38967522","citation_count":4,"is_preprint":false},{"pmid":"36657708","id":"PMC_36657708","title":"The c-Myc targeting hnRNPAB promotes lung adenocarcinoma cell proliferation via stabilization of CDK4 mRNA.","date":"2023","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36657708","citation_count":4,"is_preprint":false},{"pmid":"41144758","id":"PMC_41144758","title":"tRNA-Derived Fragment tRF-22 Promotes Immunosuppression by Inhibiting HnRNPAB Ubiquitination in Esophageal Squamous Cell Carcinoma.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41144758","citation_count":3,"is_preprint":false},{"pmid":"34555436","id":"PMC_34555436","title":"Cellular hnRNPAB interacts with avian influenza viral protein PB2 and inhibits virus replication potentially by restricting PB2 mRNA nuclear export and PB2 protein level.","date":"2021","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/34555436","citation_count":3,"is_preprint":false},{"pmid":"39976282","id":"PMC_39976282","title":"Ntoco Promotes Ferroptosis via Hnrnpab-Mediated NF-κB/Lcn2 Axis Following Traumatic Brain Injury in Mice.","date":"2025","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39976282","citation_count":3,"is_preprint":false},{"pmid":"40189014","id":"PMC_40189014","title":"KAP1 promotes gastric adenocarcinoma progression by activating Hippo/YAP1 signaling via binding to HNRNPAB.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/40189014","citation_count":2,"is_preprint":false},{"pmid":"38944160","id":"PMC_38944160","title":"hnRNPAB inhibits Influenza A virus infection by disturbing polymerase activity.","date":"2024","source":"Antiviral 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development","date":"2024-08-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.08.607197","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14407,"output_tokens":4847,"usd":0.057963,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13010,"output_tokens":4782,"usd":0.0923,"stage2_stop_reason":"end_turn"},"total_usd":0.150263,"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\": 2012,\n      \"finding\": \"hnRNP A/B knockdown in primary neurons induced alternative splicing impairments and dendrite loss, and caused memory and electrocorticographic impairments in mice; cholinergic excitation increased hnRNP A/B levels while neurotoxin-mediated destruction of cholinergic neurons caused cortical decrease in hnRNP A/B and recapitulated AD-like alternative splicing patterns, establishing cholinergic regulation of hnRNP A/B as a mechanism controlling cortical splicing.\",\n      \"method\": \"hnRNP A/B knockdown in primary neurons and mice, in vivo cholinergic neurotoxin lesion, electrocorticography, behavioral memory testing\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with defined cellular and behavioral phenotype, multiple readouts in single lab\",\n      \"pmids\": [\"22628224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila hnRNP A/B homolog Hrp48 (ortholog of HNRNPAB) binds to the 5' and 3' regions of oskar mRNA and is required for translational repression of unlocalized oskar mRNA during transport; Hrp48 levels are crucial for polarization of the oocyte during mid-oogenesis.\",\n      \"method\": \"Genetic mutant analysis (three hrp48 alleles), RNA binding assays, oocyte phenotypic analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent papers using genetic alleles, RNA binding, and functional readouts, replicated across labs\",\n      \"pmids\": [\"15130489\", \"15130488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila Hrp48 colocalizes with oskar mRNA throughout oogenesis and its loss specifically abolishes oskar mRNA posterior localization without affecting translational control, splicing, or other mRNA localizations; Hrp48 mutations disrupt GFP-Staufen particle formation, defining a new step in the localization pathway.\",\n      \"method\": \"Germline clone screen, live imaging of GFP-Staufen, genetic mutant analysis (three missense alleles), RNA localization assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent concurrent papers using genetic alleles and imaging with orthogonal readouts\",\n      \"pmids\": [\"15130488\", \"15130489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CBF-A/Hnrnpab directly binds the A2RE/RTS element in the 3' UTR of Protamine2 (Prm2) mRNA and contributes to temporal translational regulation during spermatogenesis; the p42 isoform associates with translationally active (de-repressed) Prm2 mRNA and interacts with the 5' cap complex and polysomes, whereas p37 associates with translationally repressed Prm2 mRNA; Hnrnpab knockout mice show reduced PRM2 expression and premature Prm2 translation with abnormal sperm DNA morphology.\",\n      \"method\": \"RNA immunoprecipitation, direct binding assay, polysome fractionation, 5' cap complex pulldown, Hnrnpab knockout mouse analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (direct binding, polysome fractionation, cap-complex interaction, KO mouse) in single study\",\n      \"pmids\": [\"24146628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HNRNPAB transcriptionally activates SNAIL1, which in turn represses E-cadherin transcription, thereby promoting epithelial-mesenchymal transition (EMT) and metastasis of hepatocellular carcinoma; siRNA-mediated silencing of SNAIL attenuated HNRNPAB-enhanced invasion in vitro and lung metastasis in vivo.\",\n      \"method\": \"RNA interference (siRNA), overexpression, in vitro invasion assays, in vivo lung metastasis model, reporter and ChIP assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via SNAIL knockdown rescue, in vivo metastasis model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24638979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Hnrnpab knockout mouse neural stem and progenitor cells undergo altered differentiation patterns; mature Hnrnpab(-/-) neurons show increased sensitivity to glutamate-induced excitotoxicity; Hnrnpab nucleocytoplasmic distribution in primary neurons is regulated by developmental stage.\",\n      \"method\": \"Hnrnpab knockout mouse, neural stem cell culture, glutamate excitotoxicity assay, subcellular fractionation/localization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotypes and localization experiment, single lab\",\n      \"pmids\": [\"22332140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hnrnpab regulates transcription of Eps8 in the subventricular zone; loss of Hnrnpab decreases Eps8 expression and impairs neural cell migration from the SVZ; both alternatively spliced Hnrnpab isoforms (p37 and p42) are required together (non-redundantly) to restore Eps8 transcription and cell motility.\",\n      \"method\": \"Hnrnpab knockout mouse, SVZ migration assay, RNA-seq, ectopic re-expression of individual isoforms\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined migration phenotype, RNA-seq, rescue by isoform re-expression, single lab\",\n      \"pmids\": [\"30314980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPAB interacts with influenza A virus nucleoprotein (NP) and restricts viral mRNA nuclear export by inhibiting mRNA transfer from ALY to NXF1; NP cooperates with hnRNPAB to interrupt the ALY-UAP56 interaction, repressing ALY-viral mRNA binding and nuclear export of viral mRNA.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, nuclear export assays, binding competition assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional export assays, single lab with multiple readouts\",\n      \"pmids\": [\"33681726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPAB interacts with influenza A virus NP via a 5-amino-acid peptide at its C-terminal domain (aa 318-322) to inhibit the PB1-NP interaction, thereby disrupting FluPol complex assembly and inhibiting viral polymerase activity; hnRNPAB-deficient mice show higher viral burdens and increased mortality after influenza infection.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (5-aa peptide), viral polymerase activity assay, hnRNPAB knockout mouse in vivo infection\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-level mapping of interaction interface, in vitro polymerase assay, and in vivo KO mouse validation across orthogonal methods\",\n      \"pmids\": [\"38944160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPAB associates with avian influenza viral PB2 mRNA; overexpression of hnRNPAB reduces PB2 mRNA nuclear export and PB2 protein level (without changing PB2 mRNA level), restricts viral polymerase activity, and inhibits virus replication; virus infection induces nuclear accumulation of hnRNPAB.\",\n      \"method\": \"RNA immunoprecipitation, overexpression/knockdown, mRNA nuclear export assay, viral polymerase activity assay, subcellular fractionation\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP, nuclear export assay, polymerase activity, and localization experiments, single lab\",\n      \"pmids\": [\"34555436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"lnc-CTSLP4 binds HNRNPAB within an Hsp90α/HNRNPAB complex and recruits E3-ubiquitin ligase ZFP91 to induce ubiquitination and degradation of HNRNPAB, thereby suppressing HNRNPAB-dependent transcriptional activation of Snail and reversing EMT in gastric cancer cells.\",\n      \"method\": \"RNA pull-down, co-immunoprecipitation, ubiquitination assay, gain/loss-of-function assays, peritoneal dissemination in vivo model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown, Co-IP, ubiquitination assay with defined E3 ligase, single lab\",\n      \"pmids\": [\"33717650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"tRF-22 binds to Lys91 on hnRNPAB and inhibits its ubiquitination by TRIM25, leading to hnRNPAB stabilization; stabilized hnRNPAB activates TGFB2 transcription, which promotes PMN-MDSC generation and immunosuppression in esophageal squamous cell carcinoma.\",\n      \"method\": \"RNA-protein binding assay (residue-level), ubiquitination assay, TRIM25 identification, TGFB2 transcription reporter/ChIP, immune cell infiltration analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-level binding (Lys91), ubiquitination by specific E3, transcriptional activation assay, single lab\",\n      \"pmids\": [\"41144758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPAB binds MYC mRNA and prolongs its half-life (mRNA stabilization), thereby increasing MYC protein levels and downstream CXCL8 secretion, which promotes neutrophil recruitment and facilitates liver metastasis in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay (half-life measurement), xenograft metastasis model, CXCL8 secretion assay\",\n      \"journal\": \"Molecular cancer research: MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, mRNA half-life assay, in vivo metastasis model, single lab\",\n      \"pmids\": [\"38967522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hnRNPAB is a direct transcriptional target of c-Myc (ChIP and luciferase reporter confirmed); hnRNPAB binds CDK4 mRNA and stabilizes it, increasing CDK4 protein levels and promoting G1/S cell cycle progression and lung adenocarcinoma cell proliferation; hnRNPAB mediates the proliferative effect of c-Myc.\",\n      \"method\": \"ChIP, luciferase reporter assay, RNA immunoprecipitation (RIP), flow cytometry, colony formation assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, luciferase reporter, RIP with functional cell cycle readout, single lab\",\n      \"pmids\": [\"36657708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HNRNPAB represses transcription of lnc-ELF209 by directly binding to its promoter region, as demonstrated by chromatin immunoprecipitation; lnc-ELF209 in turn inhibits HNRNPAB-promoted HCC cell migration, invasion, and EMT.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), lncRNA microarray, qRT-PCR, gain/loss-of-function assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, functional rescue assays, single lab\",\n      \"pmids\": [\"31090062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncRNA Ntoco binds Hnrnpab and facilitates K48-linked ubiquitination and degradation of Hnrnpab, suppressing NF-κB/Lcn2 signaling (reduced IkBα phosphorylation, increased IKKα/β phosphorylation, nuclear translocation of NF-κB p65, elevated Lcn2), thereby promoting ferroptosis in neurons following traumatic brain injury.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay (K48 linkage), western blotting, in vivo CCI mouse model\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown, RIP, K48 ubiquitination, pathway signaling assays, in vivo model, single lab\",\n      \"pmids\": [\"39976282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAP1 interacts with HNRNPAB as identified by mass spectrometry, further modulating YAP1 signaling in gastric adenocarcinoma.\",\n      \"method\": \"Mass spectrometry (protein interaction), co-immunoprecipitation implied\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single MS identification of interaction, limited functional follow-up on HNRNPAB specifically\",\n      \"pmids\": [\"40189014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HNRNPAB promotes back-splicing and expression of circESR1 by binding to Alu elements of cognate ESR1 pre-mRNA; HNRNPAB also binds and stabilizes CDK1 and CDK6 mRNAs, and this stabilization is facilitated by asymmetrical circESR1 binding to HNRNPAB, promoting cell cycle progression in ER+ breast cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, overexpression/knockdown, flow cytometry for cell cycle\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, stability assay, functional cell cycle readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41608617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"tRFValCAC (a sperm-enriched tRNA fragment) interacts with hnRNPAB in the epididymis, and this interaction regulates sorting and packing of tRFValCAC into extracellular vesicles for delivery to sperm.\",\n      \"method\": \"RNA-protein interaction assay (RNA pull-down/RIP), extracellular vesicle isolation and characterization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method RNA-protein interaction, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Overexpression of duck HNRNPAB reduced MAVS-induced IFNβ promoter activity and MAVS protein abundance, identifying HNRNPAB as a negative regulator of MAVS-mediated Type I IFN signaling.\",\n      \"method\": \"Overexpression functional assay, IFNβ promoter reporter assay, western blotting for MAVS abundance\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with reporter assay, no endogenous KO/KD validation, single lab\",\n      \"pmids\": [\"41807513\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPAB is a multifunctional RNA-binding protein that acts post-transcriptionally (binding 3' UTR elements to regulate mRNA translation, stability, and nuclear export) and transcriptionally (binding gene promoters to activate or repress transcription of targets such as SNAIL1, TGFB2, and lnc-ELF209); its activity is regulated by isoform-specific differences (p37 vs. p42), post-translational modifications including ubiquitination (by TRIM25 and ZFP91), and nucleocytoplasmic redistribution; it plays defined roles in spermatogenesis (temporal Prm2 mRNA translation), neural development and migration (via Eps8 transcription), cholinergic-regulated alternative splicing in the cortex, cancer EMT/metastasis (through SNAIL and MYC mRNA stabilization), and antiviral defense (inhibiting influenza polymerase complex assembly via NP interaction and restricting viral mRNA nuclear export).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPAB is a multifunctional RNA-binding protein that acts at multiple post-transcriptional steps—translational repression, mRNA stabilization, and nuclear export—and additionally functions at the transcriptional level by binding gene promoters [#1, #3, #4]. Its ancestral RNA-handling role is captured by the Drosophila ortholog Hrp48, which binds the 5' and 3' regions of oskar mRNA to enforce translational repression during transport and is independently required for posterior oskar localization via Staufen particle assembly [#1, #2]. In mammals, HNRNPAB directly binds the A2RE/RTS element in the Prm2 3' UTR to impose temporal translational control during spermatogenesis, with isoform partitioning—the p42 isoform associating with translationally active, cap- and polysome-bound Prm2 mRNA and p37 with the repressed pool—such that knockout mice show premature Prm2 translation and abnormal sperm DNA morphology [#3]. In the nervous system, HNRNPAB controls cortical alternative splicing under cholinergic regulation, governs neural stem cell differentiation, and transcriptionally drives Eps8 to enable neuronal migration from the subventricular zone, a function requiring both p37 and p42 non-redundantly [#0, #5, #6]. In cancer, HNRNPAB promotes EMT and metastasis by transcriptionally activating SNAIL1 (repressing E-cadherin) and by binding and stabilizing oncogenic transcripts including MYC, CDK4, CDK1/CDK6, driving proliferation and metastatic phenotypes [#4, #12, #13, #17]; its abundance is set by ubiquitin-dependent degradation through the E3 ligases ZFP91 and TRIM25, modulated by competing lncRNAs and tRNA-derived fragments that bind HNRNPAB to either promote or block ubiquitination [#10, #11, #15]. In antiviral defense, HNRNPAB binds influenza nucleoprotein via a five-residue C-terminal peptide to block the PB1-NP interaction and FluPol assembly, and restricts viral mRNA nuclear export by interfering with the ALY-NXF1 transfer step, with knockout mice showing higher viral burden and mortality [#7, #8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the ancestral function of this protein family in mRNA handling by showing the ortholog both represses translation of unlocalized mRNA and is independently required for its localization.\",\n      \"evidence\": \"Drosophila hrp48 genetic alleles, RNA binding assays, and live imaging of GFP-Staufen during oogenesis\",\n      \"pmids\": [\"15130489\", \"15130488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Drosophila ortholog—does not establish human HNRNPAB binding sites or partners\", \"Translational repression and localization shown to be separable activities, but molecular basis of each not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined HNRNPAB as a regulator of cortical alternative splicing under upstream cholinergic control and linked its loss to dendritic and memory deficits, connecting the protein to neurodegeneration-relevant splicing.\",\n      \"evidence\": \"hnRNP A/B knockdown in primary neurons and mice, cholinergic neurotoxin lesion, electrocorticography, behavioral testing\",\n      \"pmids\": [\"22628224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific spliced target transcripts not enumerated\", \"Mechanism linking cholinergic signaling to hnRNP A/B level not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed HNRNPAB controls neural stem cell differentiation and neuronal excitotoxicity sensitivity, and that its nucleocytoplasmic distribution is developmentally regulated.\",\n      \"evidence\": \"Hnrnpab knockout mouse, neural stem cell culture, glutamate excitotoxicity assay, subcellular fractionation\",\n      \"pmids\": [\"22332140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets mediating differentiation phenotype unknown\", \"Signal controlling nucleocytoplasmic redistribution not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how HNRNPAB imposes temporal translational control in spermatogenesis through direct 3' UTR element binding and isoform-specific partitioning between repressed and active mRNA pools.\",\n      \"evidence\": \"RNA-IP, direct binding to A2RE/RTS element, polysome fractionation, cap-complex pulldown, Hnrnpab knockout mouse\",\n      \"pmids\": [\"24146628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis distinguishing p37 vs p42 association not defined\", \"Whether the same isoform logic applies to other mRNAs unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a transcriptional (rather than purely post-transcriptional) role: HNRNPAB activates SNAIL1 to repress E-cadherin and drive EMT and metastasis.\",\n      \"evidence\": \"siRNA, overexpression, invasion assays, in vivo lung metastasis model, reporter and ChIP assays in HCC\",\n      \"pmids\": [\"24638979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an RNA-binding protein engages the SNAIL1 promoter mechanistically unclear\", \"Cofactors for transcriptional activation not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated non-redundant cooperation of both isoforms in transcriptional control of Eps8 driving neural migration, extending the transcriptional role to development.\",\n      \"evidence\": \"Hnrnpab knockout mouse, SVZ migration assay, RNA-seq, isoform re-expression rescue\",\n      \"pmids\": [\"30314980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism requiring both isoforms together not explained\", \"Direct promoter occupancy at Eps8 not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established HNRNPAB as an antiviral restriction factor that blocks influenza viral mRNA nuclear export by interrupting the ALY-NXF1 transfer step in cooperation with viral NP.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, nuclear export and binding competition assays; separate study with avian PB2 mRNA and RNA-IP\",\n      \"pmids\": [\"33681726\", \"34555436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether restriction reflects host defense or viral hijacking of the protein not fully resolved\", \"Direct vs indirect engagement of export machinery not structurally defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed HNRNPAB abundance is set by lncRNA-scaffolded E3 ligase recruitment, defining a degradation mechanism that gates its EMT-driving transcriptional activity.\",\n      \"evidence\": \"RNA pull-down, Co-IP, ubiquitination assay identifying ZFP91 within an Hsp90α/HNRNPAB complex, peritoneal dissemination model in gastric cancer\",\n      \"pmids\": [\"33717650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination acceptor residue for ZFP91 not mapped\", \"Generality across tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the precise interaction interface (C-terminal aa 318-322) by which HNRNPAB blocks PB1-NP binding and FluPol assembly, and confirmed protective antiviral function in vivo.\",\n      \"evidence\": \"Co-IP, 5-aa domain mapping, viral polymerase activity assay, hnRNPAB knockout mouse influenza infection\",\n      \"pmids\": [\"38944160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between polymerase-assembly block and mRNA-export block not integrated\", \"Structure of the HNRNPAB-NP interface not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the oncogenic mechanism to mRNA stabilization, showing HNRNPAB prolongs MYC mRNA half-life to drive CXCL8-dependent neutrophil recruitment and liver metastasis.\",\n      \"evidence\": \"RNA-IP, mRNA half-life measurement, xenograft metastasis model, CXCL8 secretion assay in PDAC\",\n      \"pmids\": [\"38967522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA element recognized in MYC mRNA not defined\", \"Whether stabilization requires a specific isoform unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed HNRNPAB in a feed-forward proliferative circuit: it is a direct c-Myc transcriptional target that in turn stabilizes CDK4 mRNA to drive G1/S progression.\",\n      \"evidence\": \"ChIP, luciferase reporter, RIP, flow cytometry, colony formation in lung adenocarcinoma\",\n      \"pmids\": [\"36657708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CDK4 mRNA binding site not mapped\", \"Isoform dependence not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined small-RNA control of HNRNPAB stability, with tRF-22 binding Lys91 to block TRIM25-mediated ubiquitination, stabilizing HNRNPAB to activate TGFB2 transcription and immunosuppression.\",\n      \"evidence\": \"Residue-level RNA-protein binding, ubiquitination assay, TRIM25 identification, TGFB2 reporter/ChIP, immune infiltration analysis in ESCC\",\n      \"pmids\": [\"41144758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Lys91 is the TRIM25 ubiquitination acceptor or only a regulatory site unclear\", \"Interplay with ZFP91-mediated degradation not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked HNRNPAB degradation to NF-κB/Lcn2 signaling and neuronal ferroptosis, broadening its regulatory reach beyond cancer.\",\n      \"evidence\": \"RNA pull-down, RIP, Co-IP, K48 ubiquitination assay, signaling western blots, in vivo controlled cortical impact model\",\n      \"pmids\": [\"39976282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating Ntoco-directed degradation not identified\", \"Direct connection between HNRNPAB and NF-κB pathway components not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed HNRNPAB can promote back-splicing of circRNA and couple a circRNA cofactor to mRNA stabilization, integrating circular and linear RNA regulation in cell cycle control.\",\n      \"evidence\": \"RIP, mRNA stability assay, overexpression/knockdown, flow cytometry in ER+ breast cancer\",\n      \"pmids\": [\"41608617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Alu-element-directed back-splicing not detailed\", \"Stoichiometry of circESR1-HNRNPAB-CDK mRNA complex not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPAB switches between repressing translation, stabilizing mRNA, controlling nuclear export, and binding promoters—and what determines this functional partitioning across isoforms, modifications, and subcellular compartments—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HNRNPAB on its RNA or promoter targets\", \"Rules governing p37 vs p42 functional specialization not unified\", \"Mechanism by which an RNA-binding protein engages chromatin/promoters not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 12, 13, 17]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 6, 11, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 12, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 12, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NP\", \"TRIM25\", \"ZFP91\", \"KAP1\", \"HSP90AA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}