{"gene":"HNRNPA0","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2014,"finding":"HNRNPA0 is an RNA-binding protein that regulates mRNA stability by binding to AU-rich elements (AREs) of target mRNAs; knockdown of Hnrnpa0 in murine hematopoietic cells disproportionately impacts AU-rich containing transcripts and shifts myeloid cell fate from monocytic toward granulocytic differentiation.","method":"RNAi knockdown in primary murine cells, microarray-based global expression profiling","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and genome-wide transcript profiling, single lab","pmids":["24532040"],"is_preprint":false},{"year":2024,"finding":"hnRNPA0 overexpression inhibits HIV-1 replication through multiple mechanisms: it reduces Tat-driven LTR transcriptional activity, retains unspliced HIV-1 mRNA in the nucleus (reducing export), and impairs programmed ribosomal frameshifting efficiency, shifting the p55/p15 ratio. Conversely, hnRNPA0 knockdown increases LTR activity and unspliced mRNA export.","method":"Knockdown and overexpression in HIV-1-infected cells (THP-1, Jurkat), LTR reporter assays, mRNA fractionation, ribosomal frameshifting assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (LTR reporter, mRNA fractionation, frameshifting), single lab","pmids":["38899932"],"is_preprint":false},{"year":2024,"finding":"hnRNPA0 binds the enhancer lncRNA MY34UE-AS through its RRM2 domain, and this interaction promotes MYB expression as well as proliferation and migration of human leukemia (K562) cells; hnRNPA0 overexpression upregulates MYB, while knockdown shows opposite effects, and rescue experiments confirm MY34UE-AS is required for hnRNPA0's effects.","method":"RNA pulldown, RNA immunoprecipitation (RIP), domain mapping, overexpression/knockdown with functional rescue in K562 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal RNA pulldown and RIP with domain mapping plus functional rescue, single lab","pmids":["38865811"],"is_preprint":false},{"year":2025,"finding":"hnRNPA0 binds directly to the 3'-UTR of CCR2 mRNA and destabilizes it; mutagenesis of RBP binding sites in the CCR2 3'-UTR or CRISPR-Cas9-mediated removal of the 3'-UTR increased CCR2 mRNA half-life (~2-fold), mRNA levels, and protein levels in both nuclear and cytoplasmic fractions of primary CD4+ T cells and macrophages.","method":"Direct binding assay, CRISPR-Cas9 3'-UTR deletion, α-amanitin mRNA stability assay, cell fractionation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding, genetic deletion, functional mRNA stability assay with fractionation; single lab","pmids":["40909274"],"is_preprint":false},{"year":2026,"finding":"The lncRNA LHFPL3-AS2 directly binds hnRNPA0 protein and enhances its interaction with kinase MAPKAP-K2 (MK2), promoting MK2-mediated phosphorylation of hnRNPA0 at serine 84; phosphorylated hnRNPA0 binds and stabilizes oncogenic transcripts including BMP7 mRNA, elevating their expression in ESCC cells.","method":"RNA-protein binding assay, Co-IP to map hnRNPA0–MK2 interaction, phosphorylation assay (serine 84), mRNA stability assessment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation mapping at specific residue, mRNA binding and stability; single lab","pmids":["41707979"],"is_preprint":false},{"year":2026,"finding":"Influenza B virus NS1 protein physically interacts with hnRNPA0; the interaction was mapped to the NS1-RBD and NS1-ED domains of NS1 and the GRD domain of hnRNPA0, confirmed by Co-IP, immunofluorescence assay (IFA), and bimolecular fluorescence complementation (BiFC).","method":"Pull-down/LC-MS/MS, Co-IP, IFA, BiFC, domain mapping","journal":"Virus genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods (Co-IP, IFA, BiFC) with domain mapping; single lab","pmids":["41817792"],"is_preprint":false},{"year":2025,"finding":"miR-424-3p targets HNRNPA0, and this targeting upregulates p53 and suppresses ferroptosis inhibitors SLC7A11 and GPX4, thereby inhibiting adipogenesis in 3T3-L1 cells; HNRNPA0 overexpression reverses these effects, restoring lipid storage capacity.","method":"miRNA overexpression/inhibition, HNRNPA0 overexpression rescue, lipidomic analysis, ROS/GSH measurement in 3T3-L1 cells","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional rescue with overexpression but no direct binding validation of miR-424-3p→HNRNPA0 site; single lab, single study","pmids":["41381030"],"is_preprint":false},{"year":2024,"finding":"Computational analysis of ENCODE knockdown datasets indicates that hnRNPA0 predominantly regulates exon inclusion in concert with other RNA-binding proteins (interdependent regulation) rather than acting independently, classifying it as a minor influencer of alternative splicing.","method":"Computational analysis of ENCODE RBP knockdown and eCLIP binding datasets (HepG2, K562)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatic analysis only, no direct biochemical experiment on HNRNPA0","pmids":[],"is_preprint":true}],"current_model":"HNRNPA0 is a nuclear RNA-binding protein (containing RRM domains including RRM2) that regulates mRNA stability and gene expression by binding AU-rich elements (AREs) in 3'-UTRs of target mRNAs; its activity is modulated by MAPKAP-K2-mediated phosphorylation at serine 84 (promoted by lncRNA scaffolding), it interacts with lncRNAs to regulate transcription factor expression, suppresses HIV-1 replication by inhibiting LTR activity, nuclear mRNA export, and ribosomal frameshifting, and contributes to myeloid cell fate determination through ARE-dependent transcript stabilization."},"narrative":{"mechanistic_narrative":"HNRNPA0 is a nuclear RNA-binding protein that controls gene expression post-transcriptionally by binding AU-rich elements (AREs) in target mRNA 3'-UTRs and dictating transcript stability [PMID:24532040]. Through ARE-dependent regulation it biases hematopoietic differentiation, with loss disproportionately affecting AU-rich transcripts and shifting myeloid fate from monocytic toward granulocytic [PMID:24532040]. Its destabilizing activity is direct and sequence-specific: hnRNPA0 binds the CCR2 3'-UTR and shortens CCR2 mRNA half-life, an effect abolished by mutation or CRISPR deletion of the binding region [PMID:40909274]. The protein's output is reprogrammed by lncRNA scaffolding and phosphorylation—the lncRNA LHFPL3-AS2 binds hnRNPA0 and enhances its association with the kinase MAPKAP-K2 (MK2), driving phosphorylation at serine 84, after which hnRNPA0 stabilizes rather than degrades oncogenic transcripts such as BMP7 [PMID:41707979]. hnRNPA0 also engages lncRNAs through its RRM2 domain, binding the enhancer lncRNA MY34UE-AS to promote MYB expression and leukemia cell proliferation [PMID:38865811]. Beyond endogenous mRNAs, hnRNPA0 restricts HIV-1 by reducing Tat-driven LTR transcription, retaining unspliced viral mRNA in the nucleus, and impairing programmed ribosomal frameshifting [PMID:38899932], and it is targeted by influenza B virus NS1 via its GRD domain [PMID:41817792]. Together these findings define hnRNPA0 as a context-dependent ARE/lncRNA-binding regulator whose stabilizing versus destabilizing behavior is set by its protein and RNA partners.","teleology":[{"year":2014,"claim":"Established hnRNPA0 as an ARE-binding regulator of mRNA stability with a defined developmental consequence, linking its molecular activity to myeloid cell fate.","evidence":"RNAi knockdown in primary murine hematopoietic cells with genome-wide microarray profiling","pmids":["24532040"],"confidence":"Medium","gaps":["Specific ARE-containing transcripts driving the fate shift not individually validated","No direct binding site mapping on endogenous targets","Stabilizing vs destabilizing mode not resolved here"]},{"year":2024,"claim":"Demonstrated hnRNPA0 acts as an HIV-1 restriction factor through several distinct steps of the viral life cycle, extending its role from mRNA stability to transcription, export, and translational recoding.","evidence":"Knockdown/overexpression in THP-1 and Jurkat cells with LTR reporter, mRNA fractionation, and ribosomal frameshifting assays","pmids":["38899932"],"confidence":"Medium","gaps":["Direct RNA target/binding sites on HIV-1 transcripts not mapped","Mechanism linking nuclear retention to frameshifting effect unclear","Whether endogenous hnRNPA0 levels matter in physiological infection untested"]},{"year":2024,"claim":"Identified RRM2 as the lncRNA-binding module and connected hnRNPA0–lncRNA interaction to transcription factor (MYB) induction and leukemia cell growth.","evidence":"RNA pulldown, RIP, domain mapping, and overexpression/knockdown with functional rescue in K562 cells","pmids":["38865811"],"confidence":"Medium","gaps":["Mechanism by which the lncRNA interaction upregulates MYB not defined","Whether RRM2 lncRNA binding competes with ARE-mRNA binding unknown"]},{"year":2025,"claim":"Provided direct genetic evidence that hnRNPA0 destabilizes a specific endogenous mRNA via its 3'-UTR, confirming a causal destabilizing mechanism.","evidence":"Direct binding assay, CRISPR-Cas9 3'-UTR deletion, α-amanitin stability assay, and fractionation in CD4+ T cells and macrophages","pmids":["40909274"],"confidence":"Medium","gaps":["Decay machinery recruited by hnRNPA0 not identified","Generality across other ARE targets not established"]},{"year":2025,"claim":"Placed HNRNPA0 in a miRNA-controlled circuit affecting p53/ferroptosis and adipogenesis, broadening its functional reach to lipid metabolism.","evidence":"miR-424-3p overexpression/inhibition with HNRNPA0 rescue, lipidomics, and ROS/GSH measurement in 3T3-L1 cells","pmids":["41381030"],"confidence":"Low","gaps":["No direct validation of miR-424-3p binding site on HNRNPA0","Mechanistic link between hnRNPA0 and p53/SLC7A11/GPX4 not defined","Single study, single cell model"]},{"year":2026,"claim":"Resolved how hnRNPA0 activity is switched toward transcript stabilization, showing a lncRNA scaffold promotes MK2-mediated Ser84 phosphorylation that licenses binding and stabilization of oncogenic mRNAs.","evidence":"RNA-protein binding assay, Co-IP mapping of hnRNPA0–MK2, Ser84 phosphorylation assay, and mRNA stability assessment in ESCC cells","pmids":["41707979"],"confidence":"Medium","gaps":["Structural basis for phosphorylation-dependent binding switch unknown","Whether the same residue governs destabilizing vs stabilizing behavior across targets untested","Single lab, single tumor context"]},{"year":2026,"claim":"Mapped a physical interface between influenza B NS1 and hnRNPA0, identifying the GRD domain as a viral hijacking site.","evidence":"Pull-down/LC-MS/MS, Co-IP, immunofluorescence, and BiFC with domain mapping","pmids":["41817792"],"confidence":"Medium","gaps":["Functional consequence of the NS1–hnRNPA0 interaction for viral replication not established","Effect on hnRNPA0 RNA-binding activity unknown"]},{"year":null,"claim":"How hnRNPA0 chooses between destabilizing and stabilizing fates for ARE-containing transcripts, and the genome-wide direct binding landscape, remain unresolved.","evidence":"No direct transcriptome-wide CLIP-based binding map or decay-machinery linkage in the available corpus","pmids":[],"confidence":"Low","gaps":["No reported eCLIP/iCLIP direct binding atlas for hnRNPA0 itself","Decay vs stabilization decision logic uncharacterized","No structural model of RRM/GRD domain function"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,4]}],"complexes":[],"partners":["MAPKAPK2","LHFPL3-AS2","MY34UE-AS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13151","full_name":"Heterogeneous nuclear ribonucleoprotein A0","aliases":[],"length_aa":305,"mass_kda":30.8,"function":"mRNA-binding component of ribonucleosomes. Specifically binds AU-rich element (ARE)-containing mRNAs. Involved in post-transcriptional regulation of cytokines mRNAs","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPA0","classification":"Not Classified","n_dependent_lines":131,"n_total_lines":1208,"dependency_fraction":0.10844370860927152},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000177733","cell_line_id":"CID001019","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"DDX21","stoichiometry":4.0},{"gene":"HNRNPL","stoichiometry":4.0},{"gene":"SNRPA","stoichiometry":4.0},{"gene":"SNRPC","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001019","total_profiled":1310},"omim":[{"mim_id":"609409","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A0; HNRNPA0","url":"https://www.omim.org/entry/609409"}],"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/HNRNPA0"},"hgnc":{"alias_symbol":[],"prev_symbol":["HNRPA0"]},"alphafold":{"accession":"Q13151","domains":[{"cath_id":"3.30.70.330","chopping":"3-82","consensus_level":"high","plddt":93.0541,"start":3,"end":82},{"cath_id":"3.30.70.330","chopping":"98-174","consensus_level":"high","plddt":92.9332,"start":98,"end":174}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13151","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13151-F1-predicted_aligned_error_v6.png","plddt_mean":71.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPA0","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPA0"},"sequence":{"accession":"Q13151","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13151"}},"corpus_meta":[{"pmid":"25716654","id":"PMC_25716654","title":"Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers.","date":"2015","source":"Familial cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25716654","citation_count":27,"is_preprint":false},{"pmid":"24532040","id":"PMC_24532040","title":"Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts.","date":"2014","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/24532040","citation_count":24,"is_preprint":false},{"pmid":"34821009","id":"PMC_34821009","title":"LncRNA miR205HG hinders HNRNPA0 translation: anti-oncogenic effects in esophageal carcinoma.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34821009","citation_count":16,"is_preprint":false},{"pmid":"24246049","id":"PMC_24246049","title":"Transcriptional analysis of hnRNPA0, A1, A2, B1, and A3 in lung cancer cell lines in response to acidosis, hypoxia, and serum deprivation conditions.","date":"2013","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/24246049","citation_count":16,"is_preprint":false},{"pmid":"38899932","id":"PMC_38899932","title":"The interferon-regulated host factor hnRNPA0 modulates HIV-1 production by interference with LTR activity, mRNA trafficking, and programmed ribosomal frameshifting.","date":"2024","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/38899932","citation_count":7,"is_preprint":false},{"pmid":"38865811","id":"PMC_38865811","title":"hnRNPA0 promotes MYB expression by interacting with enhancer lncRNA MY34UE-AS in human leukemia cells.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38865811","citation_count":3,"is_preprint":false},{"pmid":"40909274","id":"PMC_40909274","title":"The role of the 3'-UTR of the chemokine receptor CCR2 and hnRNPA0 in regulating mRNA stability and subcellular distribution in human CD4+ T cells.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40909274","citation_count":2,"is_preprint":false},{"pmid":"41381030","id":"PMC_41381030","title":"MiR-424-3p suppresses adipogenesis via HNRNPA0 targeting and p53-mediated ferroptosis.","date":"2025","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/41381030","citation_count":1,"is_preprint":false},{"pmid":"41707979","id":"PMC_41707979","title":"Starvation-induced LHFPL3-AS2 promotes MAPKAP K2-dependent phosphorylation of hnRNPA0 and progression of esophageal squamous cell carcinoma.","date":"2026","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41707979","citation_count":0,"is_preprint":false},{"pmid":"41817792","id":"PMC_41817792","title":"Screening for influenza B virus NS1-interacting host proteins and characterization of interactions with hnRNPA0 and DDX39B.","date":"2026","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/41817792","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.19.608666","title":"Interdependent regulation of alternative splicing by SR and hnRNP proteins","date":"2024-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.19.608666","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7860,"output_tokens":2079,"usd":0.027383,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9069,"output_tokens":2946,"usd":0.059498,"stage2_stop_reason":"end_turn"},"total_usd":0.086881,"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\": 2014,\n      \"finding\": \"HNRNPA0 is an RNA-binding protein that regulates mRNA stability by binding to AU-rich elements (AREs) of target mRNAs; knockdown of Hnrnpa0 in murine hematopoietic cells disproportionately impacts AU-rich containing transcripts and shifts myeloid cell fate from monocytic toward granulocytic differentiation.\",\n      \"method\": \"RNAi knockdown in primary murine cells, microarray-based global expression profiling\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and genome-wide transcript profiling, single lab\",\n      \"pmids\": [\"24532040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPA0 overexpression inhibits HIV-1 replication through multiple mechanisms: it reduces Tat-driven LTR transcriptional activity, retains unspliced HIV-1 mRNA in the nucleus (reducing export), and impairs programmed ribosomal frameshifting efficiency, shifting the p55/p15 ratio. Conversely, hnRNPA0 knockdown increases LTR activity and unspliced mRNA export.\",\n      \"method\": \"Knockdown and overexpression in HIV-1-infected cells (THP-1, Jurkat), LTR reporter assays, mRNA fractionation, ribosomal frameshifting assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (LTR reporter, mRNA fractionation, frameshifting), single lab\",\n      \"pmids\": [\"38899932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPA0 binds the enhancer lncRNA MY34UE-AS through its RRM2 domain, and this interaction promotes MYB expression as well as proliferation and migration of human leukemia (K562) cells; hnRNPA0 overexpression upregulates MYB, while knockdown shows opposite effects, and rescue experiments confirm MY34UE-AS is required for hnRNPA0's effects.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation (RIP), domain mapping, overexpression/knockdown with functional rescue in K562 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal RNA pulldown and RIP with domain mapping plus functional rescue, single lab\",\n      \"pmids\": [\"38865811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPA0 binds directly to the 3'-UTR of CCR2 mRNA and destabilizes it; mutagenesis of RBP binding sites in the CCR2 3'-UTR or CRISPR-Cas9-mediated removal of the 3'-UTR increased CCR2 mRNA half-life (~2-fold), mRNA levels, and protein levels in both nuclear and cytoplasmic fractions of primary CD4+ T cells and macrophages.\",\n      \"method\": \"Direct binding assay, CRISPR-Cas9 3'-UTR deletion, α-amanitin mRNA stability assay, cell fractionation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, genetic deletion, functional mRNA stability assay with fractionation; single lab\",\n      \"pmids\": [\"40909274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The lncRNA LHFPL3-AS2 directly binds hnRNPA0 protein and enhances its interaction with kinase MAPKAP-K2 (MK2), promoting MK2-mediated phosphorylation of hnRNPA0 at serine 84; phosphorylated hnRNPA0 binds and stabilizes oncogenic transcripts including BMP7 mRNA, elevating their expression in ESCC cells.\",\n      \"method\": \"RNA-protein binding assay, Co-IP to map hnRNPA0–MK2 interaction, phosphorylation assay (serine 84), mRNA stability assessment\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation mapping at specific residue, mRNA binding and stability; single lab\",\n      \"pmids\": [\"41707979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Influenza B virus NS1 protein physically interacts with hnRNPA0; the interaction was mapped to the NS1-RBD and NS1-ED domains of NS1 and the GRD domain of hnRNPA0, confirmed by Co-IP, immunofluorescence assay (IFA), and bimolecular fluorescence complementation (BiFC).\",\n      \"method\": \"Pull-down/LC-MS/MS, Co-IP, IFA, BiFC, domain mapping\",\n      \"journal\": \"Virus genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods (Co-IP, IFA, BiFC) with domain mapping; single lab\",\n      \"pmids\": [\"41817792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-424-3p targets HNRNPA0, and this targeting upregulates p53 and suppresses ferroptosis inhibitors SLC7A11 and GPX4, thereby inhibiting adipogenesis in 3T3-L1 cells; HNRNPA0 overexpression reverses these effects, restoring lipid storage capacity.\",\n      \"method\": \"miRNA overexpression/inhibition, HNRNPA0 overexpression rescue, lipidomic analysis, ROS/GSH measurement in 3T3-L1 cells\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional rescue with overexpression but no direct binding validation of miR-424-3p→HNRNPA0 site; single lab, single study\",\n      \"pmids\": [\"41381030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Computational analysis of ENCODE knockdown datasets indicates that hnRNPA0 predominantly regulates exon inclusion in concert with other RNA-binding proteins (interdependent regulation) rather than acting independently, classifying it as a minor influencer of alternative splicing.\",\n      \"method\": \"Computational analysis of ENCODE RBP knockdown and eCLIP binding datasets (HepG2, K562)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatic analysis only, no direct biochemical experiment on HNRNPA0\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"HNRNPA0 is a nuclear RNA-binding protein (containing RRM domains including RRM2) that regulates mRNA stability and gene expression by binding AU-rich elements (AREs) in 3'-UTRs of target mRNAs; its activity is modulated by MAPKAP-K2-mediated phosphorylation at serine 84 (promoted by lncRNA scaffolding), it interacts with lncRNAs to regulate transcription factor expression, suppresses HIV-1 replication by inhibiting LTR activity, nuclear mRNA export, and ribosomal frameshifting, and contributes to myeloid cell fate determination through ARE-dependent transcript stabilization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPA0 is a nuclear RNA-binding protein that controls gene expression post-transcriptionally by binding AU-rich elements (AREs) in target mRNA 3'-UTRs and dictating transcript stability [#0]. Through ARE-dependent regulation it biases hematopoietic differentiation, with loss disproportionately affecting AU-rich transcripts and shifting myeloid fate from monocytic toward granulocytic [#0]. Its destabilizing activity is direct and sequence-specific: hnRNPA0 binds the CCR2 3'-UTR and shortens CCR2 mRNA half-life, an effect abolished by mutation or CRISPR deletion of the binding region [#3]. The protein's output is reprogrammed by lncRNA scaffolding and phosphorylation\\u2014the lncRNA LHFPL3-AS2 binds hnRNPA0 and enhances its association with the kinase MAPKAP-K2 (MK2), driving phosphorylation at serine 84, after which hnRNPA0 stabilizes rather than degrades oncogenic transcripts such as BMP7 [#4]. hnRNPA0 also engages lncRNAs through its RRM2 domain, binding the enhancer lncRNA MY34UE-AS to promote MYB expression and leukemia cell proliferation [#2]. Beyond endogenous mRNAs, hnRNPA0 restricts HIV-1 by reducing Tat-driven LTR transcription, retaining unspliced viral mRNA in the nucleus, and impairing programmed ribosomal frameshifting [#1], and it is targeted by influenza B virus NS1 via its GRD domain [#5]. Together these findings define hnRNPA0 as a context-dependent ARE/lncRNA-binding regulator whose stabilizing versus destabilizing behavior is set by its protein and RNA partners.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established hnRNPA0 as an ARE-binding regulator of mRNA stability with a defined developmental consequence, linking its molecular activity to myeloid cell fate.\",\n      \"evidence\": \"RNAi knockdown in primary murine hematopoietic cells with genome-wide microarray profiling\",\n      \"pmids\": [\"24532040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ARE-containing transcripts driving the fate shift not individually validated\",\n        \"No direct binding site mapping on endogenous targets\",\n        \"Stabilizing vs destabilizing mode not resolved here\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated hnRNPA0 acts as an HIV-1 restriction factor through several distinct steps of the viral life cycle, extending its role from mRNA stability to transcription, export, and translational recoding.\",\n      \"evidence\": \"Knockdown/overexpression in THP-1 and Jurkat cells with LTR reporter, mRNA fractionation, and ribosomal frameshifting assays\",\n      \"pmids\": [\"38899932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct RNA target/binding sites on HIV-1 transcripts not mapped\",\n        \"Mechanism linking nuclear retention to frameshifting effect unclear\",\n        \"Whether endogenous hnRNPA0 levels matter in physiological infection untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified RRM2 as the lncRNA-binding module and connected hnRNPA0\\u2013lncRNA interaction to transcription factor (MYB) induction and leukemia cell growth.\",\n      \"evidence\": \"RNA pulldown, RIP, domain mapping, and overexpression/knockdown with functional rescue in K562 cells\",\n      \"pmids\": [\"38865811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which the lncRNA interaction upregulates MYB not defined\",\n        \"Whether RRM2 lncRNA binding competes with ARE-mRNA binding unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided direct genetic evidence that hnRNPA0 destabilizes a specific endogenous mRNA via its 3'-UTR, confirming a causal destabilizing mechanism.\",\n      \"evidence\": \"Direct binding assay, CRISPR-Cas9 3'-UTR deletion, \\u03b1-amanitin stability assay, and fractionation in CD4+ T cells and macrophages\",\n      \"pmids\": [\"40909274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Decay machinery recruited by hnRNPA0 not identified\",\n        \"Generality across other ARE targets not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed HNRNPA0 in a miRNA-controlled circuit affecting p53/ferroptosis and adipogenesis, broadening its functional reach to lipid metabolism.\",\n      \"evidence\": \"miR-424-3p overexpression/inhibition with HNRNPA0 rescue, lipidomics, and ROS/GSH measurement in 3T3-L1 cells\",\n      \"pmids\": [\"41381030\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct validation of miR-424-3p binding site on HNRNPA0\",\n        \"Mechanistic link between hnRNPA0 and p53/SLC7A11/GPX4 not defined\",\n        \"Single study, single cell model\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved how hnRNPA0 activity is switched toward transcript stabilization, showing a lncRNA scaffold promotes MK2-mediated Ser84 phosphorylation that licenses binding and stabilization of oncogenic mRNAs.\",\n      \"evidence\": \"RNA-protein binding assay, Co-IP mapping of hnRNPA0\\u2013MK2, Ser84 phosphorylation assay, and mRNA stability assessment in ESCC cells\",\n      \"pmids\": [\"41707979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for phosphorylation-dependent binding switch unknown\",\n        \"Whether the same residue governs destabilizing vs stabilizing behavior across targets untested\",\n        \"Single lab, single tumor context\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped a physical interface between influenza B NS1 and hnRNPA0, identifying the GRD domain as a viral hijacking site.\",\n      \"evidence\": \"Pull-down/LC-MS/MS, Co-IP, immunofluorescence, and BiFC with domain mapping\",\n      \"pmids\": [\"41817792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the NS1\\u2013hnRNPA0 interaction for viral replication not established\",\n        \"Effect on hnRNPA0 RNA-binding activity unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How hnRNPA0 chooses between destabilizing and stabilizing fates for ARE-containing transcripts, and the genome-wide direct binding landscape, remain unresolved.\",\n      \"evidence\": \"No direct transcriptome-wide CLIP-based binding map or decay-machinery linkage in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reported eCLIP/iCLIP direct binding atlas for hnRNPA0 itself\",\n        \"Decay vs stabilization decision logic uncharacterized\",\n        \"No structural model of RRM/GRD domain function\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAPKAPK2\", \"LHFPL3-AS2\", \"MY34UE-AS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}