{"gene":"HNRNPA3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2016,"finding":"hnRNPA3 specifically binds to the G4C2 (GGGGCC) repeat RNA of C9orf72, and reduction of nuclear hnRNPA3 leads to increased repeat RNA levels as well as increased dipeptide repeat protein (DPR) production and deposition in primary neurons and patient fibroblasts.","method":"RNA binding assays, knockdown experiments in primary neurons and patient-derived fibroblasts, immunostaining of patient hippocampal tissue","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss-of-function with defined molecular phenotype replicated across multiple cell models and patient tissue, independently corroborated by subsequent studies","pmids":["27461252"],"is_preprint":false},{"year":2019,"finding":"hnRNPA3 also binds to the antisense C9orf72 repeat RNA, and both sense and antisense DPR production are increased upon hnRNPA3 reduction. Poly-GA sequesters hnRNPA3 in cytoplasmic inclusions, depleting nuclear hnRNPA3, which in turn increases DPR production and exacerbates DNA double-strand breaks.","method":"RNA binding assays (antisense repeat RNA), siRNA knockdown, immunofluorescence co-localization of hnRNPA3 with poly-GA inclusions, γH2AX/pATM foci analysis in patient dentate gyri","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple orthogonal phenotypic readouts (DPR levels, DNA damage foci) and patient tissue validation","pmids":["31642962"],"is_preprint":false},{"year":2017,"finding":"hnRNPA3 is significantly mislocalized from the nucleus to the cytoplasm in spinal motor neurons of ALS patients carrying C9orf72 repeat expansions, while hnRNPA1 and hnRNPA2/B1 show no differential localization, implicating hnRNPA3 specifically in C9orf72-linked pathology.","method":"Immunostaining of ALS patient spinal cord tissue; mutation screening of HNRNPA3 coding region (no causative mutations found in Australian ALS cohort)","journal":"Neuro-degenerative diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunostaining in patient tissue, replicated across C9orf72-positive cases, but no functional rescue experiment","pmids":["29131108"],"is_preprint":false},{"year":2021,"finding":"hnRNPA3 interacts with mutant FUS in an RNA-dependent manner and is sequestered into cytoplasmic FUS inclusions (mFAs) but is not recruited to physiological stress granules, identifying it as a mFA-specific component. Silencing of the Drosophila hnRNPA3 ortholog was deleterious and potentiated human FUS toxicity in the fly retina.","method":"Affinity purification of mFAs vs. physiological SGs followed by proteomics; validation by co-immunoprecipitation; RNA-dependence confirmed by RNase treatment; Drosophila genetic knockdown with FUS toxicity readout","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal affinity purification + proteomics + genetic epistasis in Drosophila, multiple orthogonal methods in one study","pmids":["34915152"],"is_preprint":false},{"year":2021,"finding":"HNRNPA3 physically interacts with the CPSF (Cleavage and Polyadenylation Specificity Factor) complex and promotes site-specific intronic polyadenylation (IpA) at the first intron of GRHL3, suppressing full-length GRHL3 expression and thereby maintaining keratinocyte progenitor identity.","method":"Targeted genetic screen, CRISPR knockout of GRHL3 IpA site, HNRNPA3 interaction with CPSF identified by co-immunoprecipitation/pulldown, functional differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR functional validation combined with protein interaction assay and defined cellular phenotype, multiple orthogonal methods","pmids":["33469008"],"is_preprint":false},{"year":2023,"finding":"Elevated expression of hnRNPA3 in a Drosophila model of C9-ALS/FTD reduces the level of GGGGCC repeat RNA, suppresses RNA foci and DPR accumulation, and mitigates neurodegeneration, demonstrating that hnRNPA3 negatively regulates GGGGCC repeat RNA levels in vivo.","method":"Drosophila transgenic overexpression of human hnRNPA3, RT-qPCR for repeat RNA levels, immunostaining for RNA foci and DPR, neurodegeneration scoring","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with multiple molecular readouts in a single lab Drosophila model","pmids":["36611007"],"is_preprint":false},{"year":2024,"finding":"HNRNPA3 functions as a putative m6A reader that recognizes m6A modifications on AML1-ETO pre-mRNA and regulates its alternative splicing. Neratinib covalently inhibits HNRNPA3, blocking this m6A reading activity and reducing AML1-ETO protein levels to promote differentiation of t(8;21) AML cells.","method":"Covalent probe-based target identification, m6A reader functional assay, alternative splicing analysis, AML cell differentiation assays upon HNRNPA3 inhibition","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional inhibitor with defined molecular target and splicing readout in a single lab study","pmids":["38797229"],"is_preprint":false},{"year":2024,"finding":"SARS-CoV-2 N protein induces autophagic degradation of hnRNPA3 (along with Dicer, XPO5, and SRSF3), inhibiting RNA splicing; knockdown of hnRNPA3 increases N protein-induced pneumonia severity while overexpression decreases it.","method":"Protein degradation assays (autophagy inhibitor rescue), hnRNPA3 knockdown and overexpression in cell and mouse models with pneumonia severity readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in both cell and mouse models, but hnRNPA3 is studied alongside three other proteins making specific attribution partial","pmids":["39138195"],"is_preprint":false},{"year":2024,"finding":"HNRNPA3 physically interacts with PEDV NSP9 (identified by LC-MS/MS). Knockdown of HNRNPA3 promotes PEDV replication by enhancing cellular lipid synthesis via increased SREBF1 transcriptional activity through ZNF135 and activation of PI3K/AKT and JNK signaling pathways.","method":"LC-MS/MS identification of NSP9 interactors, siRNA knockdown, lipid accumulation assays, SREBF1 reporter assays, pathway inhibitor experiments","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass-spectrometry interaction plus loss-of-function with defined molecular pathway readout, single lab","pmids":["38259103"],"is_preprint":false},{"year":2025,"finding":"hnRNPA3 directly interacts with GLI2 protein (by co-immunoprecipitation and mass spectrometry), inhibiting FBXW11-mediated ubiquitination and proteasomal degradation of GLI2, thereby stabilizing GLI2 and activating Hedgehog signaling to promote HCC cell proliferation.","method":"Co-IP, LC-MS/MS, ubiquitination assays, dual-luciferase reporter, CCK8/colony formation assays, xenograft mouse model, GLI1/2 pharmacological inhibition (GANT61) rescue","journal":"Hepatology international","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstitution of ubiquitination pathway with Co-IP, MS, ubiquitination assay, and functional rescue in vitro and in vivo, single lab but multiple orthogonal methods","pmids":["41191267"],"is_preprint":false},{"year":2026,"finding":"ENDOU-1 overexpression induces translocation of HnRNPA3 from the nucleus to the cytoplasm during ER stress. Cytoplasmic HnRNPA3 acts as a reader of N6-methyladenosine (m6A) on the upstream open reading frame (uORF) cassette of CHOP mRNA (methylated by WTAP), suppressing uORF-mediated translational inhibition and enabling maximal CHOP translation in a p-eIF2α-independent manner.","method":"ENDOU-1 overexpression, subcellular fractionation, m6A reader assay, co-immunoprecipitation of HnRNPA3 with ENDOU-1, time-course correlation of protein dynamics, uORF reporter assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization shift with functional consequence demonstrated by m6A reader assay and translational reporter, single lab","pmids":["41902934"],"is_preprint":false},{"year":2025,"finding":"HIV-1 Vif expression induces increased SUMOylation of HNRNPA3 (and other HNRNPA/B family members) in infected cells. Depletion of HNRNPA3 leads to altered splicing of HIV-1 viral RNAs and dramatically reduced HIV-1 infectivity, indicating HNRNPA3 is required for proper HIV-1 RNA alternative splicing.","method":"Proteome-wide mass spectrometry SUMOylation screen during HIV-1 infection, biochemical validation, HNRNPA3 siRNA knockdown with HIV-1 splice isoform analysis and infectivity assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified PTM with biochemical validation and functional knockdown showing splicing and infectivity phenotype; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.03.26.645526"],"is_preprint":true}],"current_model":"HNRNPA3 is a nuclear RNA-binding protein that directly binds GGGGCC repeat RNAs (both sense and antisense) to suppress their translation into dipeptide repeat proteins; interacts with the CPSF complex to promote site-specific intronic polyadenylation; functions as an m6A reader on specific pre-mRNAs (AML1-ETO, CHOP uORF) to regulate alternative splicing and translation; stabilizes GLI2 by blocking FBXW11-mediated ubiquitination to activate Hedgehog signaling; and is required for proper HIV-1 RNA splicing, with its nuclear localization and activity regulated by partner proteins (ENDOU-1) and subject to Vif-induced SUMOylation and poly-GA-mediated cytoplasmic sequestration in disease contexts."},"narrative":{"mechanistic_narrative":"HNRNPA3 is a nuclear RNA-binding protein that governs RNA processing and translation, with a prominent role in C9orf72-linked neurodegeneration [PMID:27461252, PMID:33469008]. It directly binds both sense and antisense GGGGCC repeat RNAs of C9orf72 and negatively regulates repeat RNA levels; reducing nuclear HNRNPA3 increases repeat RNA, dipeptide repeat protein (DPR) production, and DNA double-strand breaks, whereas elevating it in vivo suppresses repeat RNA, RNA foci, DPR accumulation, and neurodegeneration [PMID:27461252, PMID:31642962, PMID:36611007]. In disease, the protein is depleted from the nucleus through cytoplasmic sequestration—by poly-GA inclusions and by RNA-dependent recruitment into mutant FUS aggregates—linking its nuclear loss to pathology [PMID:31642962, PMID:29131108, PMID:34915152]. Beyond repeat biology, HNRNPA3 shapes mRNA fate through several mechanisms: it physically associates with the CPSF complex to drive site-specific intronic polyadenylation of GRHL3, maintaining keratinocyte progenitor identity [PMID:33469008], and it acts as an m6A reader on AML1-ETO pre-mRNA to regulate alternative splicing in t(8;21) AML and on the CHOP uORF cassette to relieve translational repression during ER stress [PMID:38797229, PMID:41902934]. HNRNPA3 also stabilizes GLI2 by blocking FBXW11-mediated ubiquitination, thereby activating Hedgehog signaling to promote hepatocellular carcinoma proliferation [PMID:41191267], and is required for proper alternative splicing of viral RNAs, with its activity targeted by viral proteins through autophagic degradation and SUMOylation [PMID:39138195, PMID:bio_10.1101_2025.03.26.645526]. Its nucleocytoplasmic distribution and activity are regulated by partner proteins including ENDOU-1, which drives cytoplasmic translocation during ER stress [PMID:41902934].","teleology":[{"year":2016,"claim":"Established that HNRNPA3 directly binds the C9orf72 GGGGCC repeat RNA and acts as a brake on toxic DPR production, defining its first link to ALS/FTD pathology.","evidence":"RNA binding assays plus knockdown in primary neurons and patient fibroblasts with DPR readout and patient tissue immunostaining","pmids":["27461252"],"confidence":"High","gaps":["Mechanism by which binding lowers repeat RNA levels not resolved","Does not establish whether the effect is on transcription, stability, or transport"]},{"year":2017,"claim":"Showed HNRNPA3 is specifically mislocalized to the cytoplasm in C9orf72 ALS motor neurons, distinguishing it from related hnRNPA1/A2B1 and implicating nuclear depletion in disease.","evidence":"Immunostaining of patient spinal cord and HNRNPA3 coding-region mutation screen","pmids":["29131108"],"confidence":"Medium","gaps":["No functional rescue of mislocalization phenotype","No causative HNRNPA3 mutation identified"]},{"year":2019,"claim":"Extended the repeat model to antisense RNA and identified poly-GA-driven cytoplasmic sequestration as the mechanism depleting nuclear HNRNPA3 and exacerbating DNA damage.","evidence":"Antisense RNA binding assays, siRNA knockdown, poly-GA co-localization, and DNA damage foci in patient dentate gyri","pmids":["31642962"],"confidence":"High","gaps":["Causal chain linking nuclear depletion to DNA double-strand breaks not fully defined","Sequestration stoichiometry and reversibility unknown"]},{"year":2021,"claim":"Identified HNRNPA3 as a mutant FUS aggregate-specific component recruited in an RNA-dependent manner, generalizing its sequestration across distinct ALS proteinopathies.","evidence":"Affinity purification/proteomics of mFAs vs stress granules, Co-IP, RNase treatment, and Drosophila genetic epistasis","pmids":["34915152"],"confidence":"High","gaps":["RNA species mediating recruitment not identified","Whether sequestration drives or merely accompanies toxicity unresolved"]},{"year":2021,"claim":"Revealed a physiological RNA-processing role: HNRNPA3 works with the CPSF complex to direct intronic polyadenylation, controlling cell identity in keratinocytes.","evidence":"Genetic screen, CRISPR knockout of GRHL3 IpA site, Co-IP with CPSF, and differentiation assays","pmids":["33469008"],"confidence":"High","gaps":["Direct CPSF subunit contact not mapped","Genome-wide scope of HNRNPA3-dependent IpA not defined"]},{"year":2023,"claim":"Demonstrated in vivo that raising HNRNPA3 is protective, confirming it negatively regulates GGGGCC repeat RNA and neurodegeneration.","evidence":"Drosophila transgenic overexpression of human hnRNPA3 with repeat RNA, foci, DPR, and neurodegeneration readouts","pmids":["36611007"],"confidence":"Medium","gaps":["Single-lab Drosophila model","Therapeutic translatability to mammalian neurons untested"]},{"year":2024,"claim":"Defined HNRNPA3 as an m6A reader regulating AML1-ETO splicing and a druggable target via covalent inhibition in leukemia.","evidence":"Covalent probe target ID, m6A reader and splicing assays, and AML differentiation upon neratinib inhibition","pmids":["38797229"],"confidence":"Medium","gaps":["m6A reader designation is putative","Direct m6A-binding interface not structurally defined"]},{"year":2024,"claim":"Showed viral targeting of HNRNPA3 stability, with SARS-CoV-2 N protein driving its autophagic degradation to impair splicing and worsen disease.","evidence":"Autophagy-inhibitor rescue of degradation, knockdown/overexpression in cell and mouse pneumonia models","pmids":["39138195"],"confidence":"Medium","gaps":["HNRNPA3 studied alongside three other degraded proteins, limiting specific attribution","Splicing targets affected not identified"]},{"year":2024,"claim":"Identified HNRNPA3 as a host interactor of PEDV NSP9 that restricts viral replication by limiting lipid synthesis.","evidence":"LC-MS/MS interactor ID, siRNA knockdown, lipid and SREBF1 reporter assays, pathway inhibitor experiments","pmids":["38259103"],"confidence":"Medium","gaps":["Direct vs indirect control of SREBF1/lipid pathway unclear","Single interaction screen without reciprocal validation"]},{"year":2025,"claim":"Established a non-RNA, protein-stabilizing function: HNRNPA3 binds GLI2 and blocks its FBXW11-mediated ubiquitination to activate Hedgehog signaling in hepatocellular carcinoma.","evidence":"Co-IP, LC-MS/MS, ubiquitination assays, luciferase reporter, proliferation assays, xenograft, and GANT61 rescue","pmids":["41191267"],"confidence":"High","gaps":["How HNRNPA3 sterically blocks FBXW11 not defined","Whether RNA binding contributes to GLI2 stabilization unknown"]},{"year":2025,"claim":"Showed HIV-1 Vif induces HNRNPA3 SUMOylation and that HNRNPA3 is required for proper viral RNA splicing and infectivity.","evidence":"Proteome-wide SUMOylation MS screen, biochemical validation, knockdown with splice isoform and infectivity analysis (preprint)","pmids":["bio_10.1101_2025.03.26.645526"],"confidence":"Medium","gaps":["Functional consequence of SUMOylation on splicing not directly tested","Preprint, not yet peer-reviewed"]},{"year":2026,"claim":"Defined regulated nucleocytoplasmic shuttling: ENDOU-1 drives cytoplasmic translocation during ER stress, where HNRNPA3 reads m6A on the CHOP uORF to enable maximal CHOP translation.","evidence":"ENDOU-1 overexpression, subcellular fractionation, m6A reader and uORF reporter assays, Co-IP with ENDOU-1","pmids":["41902934"],"confidence":"Medium","gaps":["Mechanism by which ENDOU-1 triggers translocation unclear","Breadth of cytoplasmic m6A targets undefined"]},{"year":null,"claim":"How HNRNPA3's distinct activities—repeat RNA suppression, intronic polyadenylation, m6A reading, and GLI2 stabilization—are integrated and selectively deployed across cell types and stress states remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or domain-level explanation linking RNA-binding and protein-stabilizing functions","Determinants of nuclear vs cytoplasmic activity not mechanistically resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2,3,10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,6,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,9]}],"complexes":["CPSF"],"partners":["CPSF","FUS","GLI2","FBXW11","ENDOU1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51991","full_name":"Heterogeneous nuclear ribonucleoprotein A3","aliases":[],"length_aa":378,"mass_kda":39.6,"function":"Plays a role in cytoplasmic trafficking of RNA. Binds to the cis-acting response element, A2RE. May be involved in pre-mRNA splicing","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51991/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPA3","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":10.0},{"gene":"HNRNPC","stoichiometry":10.0},{"gene":"TOP1","stoichiometry":10.0},{"gene":"HNRNPH1","stoichiometry":4.0},{"gene":"HNRNPL","stoichiometry":4.0},{"gene":"IGF2BP1","stoichiometry":4.0},{"gene":"RBM14","stoichiometry":4.0},{"gene":"RBMX","stoichiometry":4.0},{"gene":"RPS16","stoichiometry":4.0},{"gene":"RTCB","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPA3","total_profiled":1310},"omim":[{"mim_id":"605372","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A3; HNRNPA3","url":"https://www.omim.org/entry/605372"},{"mim_id":"600124","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A2/B1; HNRNPA2B1","url":"https://www.omim.org/entry/600124"},{"mim_id":"300264","title":"UBIQUILIN 2; UBQLN2","url":"https://www.omim.org/entry/300264"},{"mim_id":"164017","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A1; HNRNPA1","url":"https://www.omim.org/entry/164017"}],"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/HNRNPA3"},"hgnc":{"alias_symbol":[],"prev_symbol":["HNRPA3"]},"alphafold":{"accession":"P51991","domains":[{"cath_id":"3.30.70.330","chopping":"31-110","consensus_level":"high","plddt":95.7801,"start":31,"end":110},{"cath_id":"3.30.70.330","chopping":"118-201","consensus_level":"high","plddt":93.246,"start":118,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51991","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51991-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51991-F1-predicted_aligned_error_v6.png","plddt_mean":66.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPA3","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPA3"},"sequence":{"accession":"P51991","fasta_url":"https://rest.uniprot.org/uniprotkb/P51991.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51991/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51991"}},"corpus_meta":[{"pmid":"31642962","id":"PMC_31642962","title":"Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.","date":"2019","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/31642962","citation_count":54,"is_preprint":false},{"pmid":"27461252","id":"PMC_27461252","title":"Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/27461252","citation_count":44,"is_preprint":false},{"pmid":"29131108","id":"PMC_29131108","title":"Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis.","date":"2017","source":"Neuro-degenerative diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29131108","citation_count":29,"is_preprint":false},{"pmid":"33469008","id":"PMC_33469008","title":"Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33469008","citation_count":25,"is_preprint":false},{"pmid":"34915152","id":"PMC_34915152","title":"ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity.","date":"2021","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/34915152","citation_count":22,"is_preprint":false},{"pmid":"38259103","id":"PMC_38259103","title":"PEDV inhibits HNRNPA3 expression by miR-218-5p to enhance cellular lipid accumulation and promote viral replication.","date":"2024","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/38259103","citation_count":16,"is_preprint":false},{"pmid":"37769807","id":"PMC_37769807","title":"Circ_0114581 promotes osteogenic differentiation of BMSCs via the MiR-155-5p/HNRNPA3 axis.","date":"2023","source":"Life 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36611007","citation_count":8,"is_preprint":false},{"pmid":"39138195","id":"PMC_39138195","title":"SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39138195","citation_count":7,"is_preprint":false},{"pmid":"40130711","id":"PMC_40130711","title":"Functional Landscape of hnRNPA3 in Disease Pathogenesis.","date":"2025","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/40130711","citation_count":2,"is_preprint":false},{"pmid":"41191267","id":"PMC_41191267","title":"hnRNPA3 promotes the proliferation of hepatocellular carcinoma cells by stabilizing GLI2 proteins and activating Hedgehog pathway.","date":"2025","source":"Hepatology international","url":"https://pubmed.ncbi.nlm.nih.gov/41191267","citation_count":0,"is_preprint":false},{"pmid":"42087895","id":"PMC_42087895","title":"Exploring the Role of HNRNPA3 in Breast Cancer Progression, Immune Microenvironment, and Therapeutic Sensitivity: A Multiomics and Functional Prediction Study.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/42087895","citation_count":0,"is_preprint":false},{"pmid":"41909761","id":"PMC_41909761","title":"A conserved mammalian mecciRNA, mecciATP6, regulates mitochondrial homeostasis through interaction with HNRNPA3.","date":"2026","source":"Non-coding RNA research","url":"https://pubmed.ncbi.nlm.nih.gov/41909761","citation_count":0,"is_preprint":false},{"pmid":"41902934","id":"PMC_41902934","title":"ENDOU-1-induced cytoplasmic HnRNPA3 recognizes m6A methylation on the upstream reading frame of human CHOP transcripts to achieve maximal CHOP translation.","date":"2026","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41902934","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.26.645526","title":"HIV-1 infection induces Vif-mediated SUMOylation of host RNA splicing factors important for proper viral RNA splicing","date":"2025-03-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.645526","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.26.615153","title":"Altered mRNA transport and local translation in iNeurons with RNA binding protein knockdown","date":"2024-09-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.26.615153","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11512,"output_tokens":3259,"usd":0.04171,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10730,"output_tokens":3936,"usd":0.076025,"stage2_stop_reason":"end_turn"},"total_usd":0.117735,"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\": 2016,\n      \"finding\": \"hnRNPA3 specifically binds to the G4C2 (GGGGCC) repeat RNA of C9orf72, and reduction of nuclear hnRNPA3 leads to increased repeat RNA levels as well as increased dipeptide repeat protein (DPR) production and deposition in primary neurons and patient fibroblasts.\",\n      \"method\": \"RNA binding assays, knockdown experiments in primary neurons and patient-derived fibroblasts, immunostaining of patient hippocampal tissue\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss-of-function with defined molecular phenotype replicated across multiple cell models and patient tissue, independently corroborated by subsequent studies\",\n      \"pmids\": [\"27461252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPA3 also binds to the antisense C9orf72 repeat RNA, and both sense and antisense DPR production are increased upon hnRNPA3 reduction. Poly-GA sequesters hnRNPA3 in cytoplasmic inclusions, depleting nuclear hnRNPA3, which in turn increases DPR production and exacerbates DNA double-strand breaks.\",\n      \"method\": \"RNA binding assays (antisense repeat RNA), siRNA knockdown, immunofluorescence co-localization of hnRNPA3 with poly-GA inclusions, γH2AX/pATM foci analysis in patient dentate gyri\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple orthogonal phenotypic readouts (DPR levels, DNA damage foci) and patient tissue validation\",\n      \"pmids\": [\"31642962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPA3 is significantly mislocalized from the nucleus to the cytoplasm in spinal motor neurons of ALS patients carrying C9orf72 repeat expansions, while hnRNPA1 and hnRNPA2/B1 show no differential localization, implicating hnRNPA3 specifically in C9orf72-linked pathology.\",\n      \"method\": \"Immunostaining of ALS patient spinal cord tissue; mutation screening of HNRNPA3 coding region (no causative mutations found in Australian ALS cohort)\",\n      \"journal\": \"Neuro-degenerative diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunostaining in patient tissue, replicated across C9orf72-positive cases, but no functional rescue experiment\",\n      \"pmids\": [\"29131108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPA3 interacts with mutant FUS in an RNA-dependent manner and is sequestered into cytoplasmic FUS inclusions (mFAs) but is not recruited to physiological stress granules, identifying it as a mFA-specific component. Silencing of the Drosophila hnRNPA3 ortholog was deleterious and potentiated human FUS toxicity in the fly retina.\",\n      \"method\": \"Affinity purification of mFAs vs. physiological SGs followed by proteomics; validation by co-immunoprecipitation; RNA-dependence confirmed by RNase treatment; Drosophila genetic knockdown with FUS toxicity readout\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal affinity purification + proteomics + genetic epistasis in Drosophila, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34915152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HNRNPA3 physically interacts with the CPSF (Cleavage and Polyadenylation Specificity Factor) complex and promotes site-specific intronic polyadenylation (IpA) at the first intron of GRHL3, suppressing full-length GRHL3 expression and thereby maintaining keratinocyte progenitor identity.\",\n      \"method\": \"Targeted genetic screen, CRISPR knockout of GRHL3 IpA site, HNRNPA3 interaction with CPSF identified by co-immunoprecipitation/pulldown, functional differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR functional validation combined with protein interaction assay and defined cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"33469008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Elevated expression of hnRNPA3 in a Drosophila model of C9-ALS/FTD reduces the level of GGGGCC repeat RNA, suppresses RNA foci and DPR accumulation, and mitigates neurodegeneration, demonstrating that hnRNPA3 negatively regulates GGGGCC repeat RNA levels in vivo.\",\n      \"method\": \"Drosophila transgenic overexpression of human hnRNPA3, RT-qPCR for repeat RNA levels, immunostaining for RNA foci and DPR, neurodegeneration scoring\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with multiple molecular readouts in a single lab Drosophila model\",\n      \"pmids\": [\"36611007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPA3 functions as a putative m6A reader that recognizes m6A modifications on AML1-ETO pre-mRNA and regulates its alternative splicing. Neratinib covalently inhibits HNRNPA3, blocking this m6A reading activity and reducing AML1-ETO protein levels to promote differentiation of t(8;21) AML cells.\",\n      \"method\": \"Covalent probe-based target identification, m6A reader functional assay, alternative splicing analysis, AML cell differentiation assays upon HNRNPA3 inhibition\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inhibitor with defined molecular target and splicing readout in a single lab study\",\n      \"pmids\": [\"38797229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SARS-CoV-2 N protein induces autophagic degradation of hnRNPA3 (along with Dicer, XPO5, and SRSF3), inhibiting RNA splicing; knockdown of hnRNPA3 increases N protein-induced pneumonia severity while overexpression decreases it.\",\n      \"method\": \"Protein degradation assays (autophagy inhibitor rescue), hnRNPA3 knockdown and overexpression in cell and mouse models with pneumonia severity readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in both cell and mouse models, but hnRNPA3 is studied alongside three other proteins making specific attribution partial\",\n      \"pmids\": [\"39138195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPA3 physically interacts with PEDV NSP9 (identified by LC-MS/MS). Knockdown of HNRNPA3 promotes PEDV replication by enhancing cellular lipid synthesis via increased SREBF1 transcriptional activity through ZNF135 and activation of PI3K/AKT and JNK signaling pathways.\",\n      \"method\": \"LC-MS/MS identification of NSP9 interactors, siRNA knockdown, lipid accumulation assays, SREBF1 reporter assays, pathway inhibitor experiments\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass-spectrometry interaction plus loss-of-function with defined molecular pathway readout, single lab\",\n      \"pmids\": [\"38259103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPA3 directly interacts with GLI2 protein (by co-immunoprecipitation and mass spectrometry), inhibiting FBXW11-mediated ubiquitination and proteasomal degradation of GLI2, thereby stabilizing GLI2 and activating Hedgehog signaling to promote HCC cell proliferation.\",\n      \"method\": \"Co-IP, LC-MS/MS, ubiquitination assays, dual-luciferase reporter, CCK8/colony formation assays, xenograft mouse model, GLI1/2 pharmacological inhibition (GANT61) rescue\",\n      \"journal\": \"Hepatology international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstitution of ubiquitination pathway with Co-IP, MS, ubiquitination assay, and functional rescue in vitro and in vivo, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41191267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ENDOU-1 overexpression induces translocation of HnRNPA3 from the nucleus to the cytoplasm during ER stress. Cytoplasmic HnRNPA3 acts as a reader of N6-methyladenosine (m6A) on the upstream open reading frame (uORF) cassette of CHOP mRNA (methylated by WTAP), suppressing uORF-mediated translational inhibition and enabling maximal CHOP translation in a p-eIF2α-independent manner.\",\n      \"method\": \"ENDOU-1 overexpression, subcellular fractionation, m6A reader assay, co-immunoprecipitation of HnRNPA3 with ENDOU-1, time-course correlation of protein dynamics, uORF reporter assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization shift with functional consequence demonstrated by m6A reader assay and translational reporter, single lab\",\n      \"pmids\": [\"41902934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIV-1 Vif expression induces increased SUMOylation of HNRNPA3 (and other HNRNPA/B family members) in infected cells. Depletion of HNRNPA3 leads to altered splicing of HIV-1 viral RNAs and dramatically reduced HIV-1 infectivity, indicating HNRNPA3 is required for proper HIV-1 RNA alternative splicing.\",\n      \"method\": \"Proteome-wide mass spectrometry SUMOylation screen during HIV-1 infection, biochemical validation, HNRNPA3 siRNA knockdown with HIV-1 splice isoform analysis and infectivity assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified PTM with biochemical validation and functional knockdown showing splicing and infectivity phenotype; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.26.645526\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"HNRNPA3 is a nuclear RNA-binding protein that directly binds GGGGCC repeat RNAs (both sense and antisense) to suppress their translation into dipeptide repeat proteins; interacts with the CPSF complex to promote site-specific intronic polyadenylation; functions as an m6A reader on specific pre-mRNAs (AML1-ETO, CHOP uORF) to regulate alternative splicing and translation; stabilizes GLI2 by blocking FBXW11-mediated ubiquitination to activate Hedgehog signaling; and is required for proper HIV-1 RNA splicing, with its nuclear localization and activity regulated by partner proteins (ENDOU-1) and subject to Vif-induced SUMOylation and poly-GA-mediated cytoplasmic sequestration in disease contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPA3 is a nuclear RNA-binding protein that governs RNA processing and translation, with a prominent role in C9orf72-linked neurodegeneration [#0, #4]. It directly binds both sense and antisense GGGGCC repeat RNAs of C9orf72 and negatively regulates repeat RNA levels; reducing nuclear HNRNPA3 increases repeat RNA, dipeptide repeat protein (DPR) production, and DNA double-strand breaks, whereas elevating it in vivo suppresses repeat RNA, RNA foci, DPR accumulation, and neurodegeneration [#0, #1, #5]. In disease, the protein is depleted from the nucleus through cytoplasmic sequestration—by poly-GA inclusions and by RNA-dependent recruitment into mutant FUS aggregates—linking its nuclear loss to pathology [#1, #2, #3]. Beyond repeat biology, HNRNPA3 shapes mRNA fate through several mechanisms: it physically associates with the CPSF complex to drive site-specific intronic polyadenylation of GRHL3, maintaining keratinocyte progenitor identity [#4], and it acts as an m6A reader on AML1-ETO pre-mRNA to regulate alternative splicing in t(8;21) AML and on the CHOP uORF cassette to relieve translational repression during ER stress [#6, #10]. HNRNPA3 also stabilizes GLI2 by blocking FBXW11-mediated ubiquitination, thereby activating Hedgehog signaling to promote hepatocellular carcinoma proliferation [#9], and is required for proper alternative splicing of viral RNAs, with its activity targeted by viral proteins through autophagic degradation and SUMOylation [#7, #11]. Its nucleocytoplasmic distribution and activity are regulated by partner proteins including ENDOU-1, which drives cytoplasmic translocation during ER stress [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that HNRNPA3 directly binds the C9orf72 GGGGCC repeat RNA and acts as a brake on toxic DPR production, defining its first link to ALS/FTD pathology.\",\n      \"evidence\": \"RNA binding assays plus knockdown in primary neurons and patient fibroblasts with DPR readout and patient tissue immunostaining\",\n      \"pmids\": [\"27461252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which binding lowers repeat RNA levels not resolved\", \"Does not establish whether the effect is on transcription, stability, or transport\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed HNRNPA3 is specifically mislocalized to the cytoplasm in C9orf72 ALS motor neurons, distinguishing it from related hnRNPA1/A2B1 and implicating nuclear depletion in disease.\",\n      \"evidence\": \"Immunostaining of patient spinal cord and HNRNPA3 coding-region mutation screen\",\n      \"pmids\": [\"29131108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue of mislocalization phenotype\", \"No causative HNRNPA3 mutation identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the repeat model to antisense RNA and identified poly-GA-driven cytoplasmic sequestration as the mechanism depleting nuclear HNRNPA3 and exacerbating DNA damage.\",\n      \"evidence\": \"Antisense RNA binding assays, siRNA knockdown, poly-GA co-localization, and DNA damage foci in patient dentate gyri\",\n      \"pmids\": [\"31642962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain linking nuclear depletion to DNA double-strand breaks not fully defined\", \"Sequestration stoichiometry and reversibility unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified HNRNPA3 as a mutant FUS aggregate-specific component recruited in an RNA-dependent manner, generalizing its sequestration across distinct ALS proteinopathies.\",\n      \"evidence\": \"Affinity purification/proteomics of mFAs vs stress granules, Co-IP, RNase treatment, and Drosophila genetic epistasis\",\n      \"pmids\": [\"34915152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA species mediating recruitment not identified\", \"Whether sequestration drives or merely accompanies toxicity unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a physiological RNA-processing role: HNRNPA3 works with the CPSF complex to direct intronic polyadenylation, controlling cell identity in keratinocytes.\",\n      \"evidence\": \"Genetic screen, CRISPR knockout of GRHL3 IpA site, Co-IP with CPSF, and differentiation assays\",\n      \"pmids\": [\"33469008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CPSF subunit contact not mapped\", \"Genome-wide scope of HNRNPA3-dependent IpA not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated in vivo that raising HNRNPA3 is protective, confirming it negatively regulates GGGGCC repeat RNA and neurodegeneration.\",\n      \"evidence\": \"Drosophila transgenic overexpression of human hnRNPA3 with repeat RNA, foci, DPR, and neurodegeneration readouts\",\n      \"pmids\": [\"36611007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Drosophila model\", \"Therapeutic translatability to mammalian neurons untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined HNRNPA3 as an m6A reader regulating AML1-ETO splicing and a druggable target via covalent inhibition in leukemia.\",\n      \"evidence\": \"Covalent probe target ID, m6A reader and splicing assays, and AML differentiation upon neratinib inhibition\",\n      \"pmids\": [\"38797229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader designation is putative\", \"Direct m6A-binding interface not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed viral targeting of HNRNPA3 stability, with SARS-CoV-2 N protein driving its autophagic degradation to impair splicing and worsen disease.\",\n      \"evidence\": \"Autophagy-inhibitor rescue of degradation, knockdown/overexpression in cell and mouse pneumonia models\",\n      \"pmids\": [\"39138195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HNRNPA3 studied alongside three other degraded proteins, limiting specific attribution\", \"Splicing targets affected not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified HNRNPA3 as a host interactor of PEDV NSP9 that restricts viral replication by limiting lipid synthesis.\",\n      \"evidence\": \"LC-MS/MS interactor ID, siRNA knockdown, lipid and SREBF1 reporter assays, pathway inhibitor experiments\",\n      \"pmids\": [\"38259103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of SREBF1/lipid pathway unclear\", \"Single interaction screen without reciprocal validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a non-RNA, protein-stabilizing function: HNRNPA3 binds GLI2 and blocks its FBXW11-mediated ubiquitination to activate Hedgehog signaling in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, LC-MS/MS, ubiquitination assays, luciferase reporter, proliferation assays, xenograft, and GANT61 rescue\",\n      \"pmids\": [\"41191267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HNRNPA3 sterically blocks FBXW11 not defined\", \"Whether RNA binding contributes to GLI2 stabilization unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed HIV-1 Vif induces HNRNPA3 SUMOylation and that HNRNPA3 is required for proper viral RNA splicing and infectivity.\",\n      \"evidence\": \"Proteome-wide SUMOylation MS screen, biochemical validation, knockdown with splice isoform and infectivity analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.26.645526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SUMOylation on splicing not directly tested\", \"Preprint, not yet peer-reviewed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined regulated nucleocytoplasmic shuttling: ENDOU-1 drives cytoplasmic translocation during ER stress, where HNRNPA3 reads m6A on the CHOP uORF to enable maximal CHOP translation.\",\n      \"evidence\": \"ENDOU-1 overexpression, subcellular fractionation, m6A reader and uORF reporter assays, Co-IP with ENDOU-1\",\n      \"pmids\": [\"41902934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ENDOU-1 triggers translocation unclear\", \"Breadth of cytoplasmic m6A targets undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPA3's distinct activities—repeat RNA suppression, intronic polyadenylation, m6A reading, and GLI2 stabilization—are integrated and selectively deployed across cell types and stress states remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or domain-level explanation linking RNA-binding and protein-stabilizing functions\", \"Determinants of nuclear vs cytoplasmic activity not mechanistically resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2, 3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 6, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"complexes\": [\"CPSF\"],\n    \"partners\": [\"CPSF\", \"FUS\", \"GLI2\", \"FBXW11\", \"ENDOU1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}