{"gene":"HNRNPA2B1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2013,"finding":"hnRNPA2B1 specifically binds exosomal miRNAs through recognition of specific sequence motifs (EXO motifs), controlling their loading into exosomes. In exosomes, hnRNPA2B1 is sumoylated, and sumoylation controls its binding to miRNAs. Mutagenesis of identified motifs or changes in hnRNPA2B1 expression levels modulate miRNA loading into exosomes.","method":"RNA immunoprecipitation, sumoylation assays, mutagenesis of miRNA motifs, modulation of hnRNPA2B1 expression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, mutagenesis validation, functional rescue, replicated concept across multiple subsequent papers","pmids":["24356509"],"is_preprint":false},{"year":2015,"finding":"HNRNPA2B1 binds m6A-bearing RNAs in vivo and in vitro with a biochemical footprint matching the m6A consensus motif, acting as a nuclear reader of the m6A mark. It mediates alternative splicing of nuclear transcripts similarly to the m6A writer METTL3, binds m6A marks in primary miRNA transcripts, interacts with the Microprocessor complex protein DGCR8, and promotes primary miRNA processing.","method":"RNA immunoprecipitation (in vivo and in vitro), alternative splicing assays, HNRNPA2B1 and METTL3 knockdown with pri-miRNA processing readout, Co-IP with DGCR8","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, in vivo RIP, parallel KD epistasis, Co-IP), replicated by multiple subsequent studies","pmids":["26321680"],"is_preprint":false},{"year":2013,"finding":"Pathogenic missense mutations in the prion-like domain (PrLD) of hnRNPA2B1 (e.g., D290V) strengthen a steric zipper motif, exacerbating formation of self-seeding fibrils that cross-seed wild-type hnRNP polymerization. Wild-type hnRNPA2 shows intrinsic tendency to assemble into self-seeding fibrils. Disease mutations promote excess incorporation into stress granules and drive cytoplasmic inclusion formation in animal models.","method":"Fibril assembly assays, seeding experiments, stress granule imaging in cells and animal models, mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro fibril reconstitution, mutagenesis, animal model validation, replicated by multiple structural and biophysical studies","pmids":["23455423"],"is_preprint":false},{"year":2018,"finding":"The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer and retains predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending the aggregation-prone region respectively. The hnRNPA2 LC domain directly interacts with and induces phase separation of TDP-43. Arginine methylation reduces hnRNPA2 phase separation by disrupting arginine-mediated contacts.","method":"NMR spectroscopy, in vitro phase separation assays, mutagenesis, arginine methylation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural characterization, mutagenesis, in vitro reconstitution of phase separation, multiple orthogonal methods in one rigorous study","pmids":["29358076"],"is_preprint":false},{"year":2019,"finding":"Upon DNA virus infection, nuclear hnRNPA2B1 senses viral DNA, homodimerizes, and is then demethylated at arginine-226 by the arginine demethylase JMJD6. This leads to hnRNPA2B1 translocation to the cytoplasm where it activates the TBK1-IRF3 pathway, inducing IFN-α/β production. Additionally, hnRNPA2B1 facilitates m6A modification and nucleocytoplasmic trafficking of CGAS, IFI16, and STING mRNAs to amplify cytoplasmic antiviral signaling.","method":"Co-IP, demethylation assays identifying JMJD6 as writer/eraser, nuclear-cytoplasmic fractionation, TBK1-IRF3 pathway activation assays, m6A RIP on CGAS/IFI16/STING mRNAs","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods identifying specific PTM writer (JMJD6), localization change with functional consequence (IFN production), mRNA trafficking assays","pmids":["31320558"],"is_preprint":false},{"year":2015,"finding":"The LC domain of hnRNPA2 adopts a similar conformation in hydrogel polymers, liquid-like droplets, and isolated nuclei, forming amyloid-like cross-β fibers. A molecular footprinting technique applied to native hnRNPA2 in isolated nuclei showed its LC domain exists in a similar polymeric conformation to recombinant polymers, suggesting biologic utility for LC domain polymerization in information transfer.","method":"Molecular footprinting of polymeric LC domain state, hydrogel polymer preparation, electron microscopy, analysis of isolated nuclei","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — novel footprinting methodology applied both in vitro and to native nuclear protein, single lab with multiple orthogonal approaches","pmids":["26544936"],"is_preprint":false},{"year":2016,"finding":"Transcriptome-wide CLIP in mouse spinal cord identified UAGG motifs enriched within ~2,500 hnRNP A2/B1 binding sites and revealed a role for hnRNP A2/B1 in alternative polyadenylation. hnRNP A2/B1 loss causes alternative splicing changes including skipping of an exon in ALS-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated D290V mutant shows increased nuclear-insoluble hnRNP A2/B1 and abnormal splicing in patient fibroblasts and iPSC-derived motor neurons.","method":"CLIP-seq in mouse spinal cord, RNA-seq upon KD, patient fibroblast and iPSC-MN analysis, nuclear fractionation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptome-wide CLIP with defined binding motifs, multiple cell types validated, disease mutation functional comparison","pmids":["27773581"],"is_preprint":false},{"year":2020,"finding":"CryoEM structure of the hnRNPA2 LCD fibril core revealed chains kinked in a cross-β conformation enabling non-covalent cross-linking of fibrils, distinguishing them from pathogenic amyloid. The D290V disease mutation fundamentally alters fibril structure to a more stable energetic state, as shown by crystal structure of the D290V-containing segment forming a steric zipper.","method":"CryoEM structure determination, crystal structure of D290V segment, hydrogel formation assay, energetic calculations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution cryoEM and crystal structures with direct comparison of wild-type vs. disease mutant fibril architecture","pmids":["32796831"],"is_preprint":false},{"year":2018,"finding":"Solid-state NMR with segmental isotope labeling showed that both wild-type hnRNPA2 LC and the D290V mutant form labile polymers in an in-register cross-β conformation. Aspartic acid 290 is charged at physiological pH and immobilized within the polymer core; D290V mutation removes destabilizing electrostatic interactions, making polymers thermodynamically more stable.","method":"Solid-state NMR spectroscopy with segmental isotope labeling, electron microscopy, thermodynamic stability measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — solid-state NMR structural characterization with mutagenesis and stability measurements, single lab with multiple orthogonal methods","pmids":["30279180"],"is_preprint":false},{"year":2021,"finding":"Optogenetically induced tau oligomers (oTau) associate with HNRNPA2B1 (identified by proteomics and validated in neurons, animal models, and human Alzheimer brain). HNRNPA2B1 functions as a linker connecting oTau with m6A-modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau from associating with m6A or reducing protein synthesis and reduces oTau-induced neurodegeneration.","method":"Optogenetic tau oligomerization (Cry2-based), proteomics, Co-IP in neurons and animal models, HNRNPA2B1 knockdown with neurodegeneration readout, m6A association assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across multiple model systems including human tissue, functional rescue experiments","pmids":["34453888"],"is_preprint":false},{"year":2014,"finding":"HNRNPA2B1 (hnRNP A2 and B1 proteins encoded by HNRNPA2B1) interacts with oncogenic KRAS G12V in PDAC cells as shown by mass spectrometry and Co-IP. This interaction requires KRAS phosphorylation at serine 181. Knockdown of HNRNPA2B1 inactivates AKT-mTOR signaling, reduces interaction between KRAS and PI3K, and reduces KRAS-dependent PDAC cell survival and tumor formation.","method":"Mass spectrometry pulldown, Co-IP, Phos-tag phosphorylation analysis, shRNA knockdown, xenograft tumor models","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS identification validated by Co-IP, phosphorylation requirement established, functional consequence in vitro and in vivo, single lab","pmids":["24998203"],"is_preprint":false},{"year":2018,"finding":"The SH3 domain of Fyn kinase (Fyn-SH3) interacts with the hnRNPA2 low-complexity domain despite hnRNPA2 lacking canonical SH3-binding sequences. Fyn-SH3 induces hnRNPA2 LC phase separation and is incorporated into in vitro phase-separated granules. NMR identified hnRNPA2 LC interaction sites on the surface of Fyn-SH3.","method":"In vitro microscopy, solution NMR spectroscopy, in vitro phase separation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization of interaction combined with in vitro phase separation microscopy, single lab with two orthogonal methods","pmids":["30397184"],"is_preprint":false},{"year":2020,"finding":"In vitro tyrosine phosphorylation of hnRNPA2 by Fyn reduces hnRNPA2 phase separation, prevents partitioning of hnRNPF and ch-TOG into hnRNPA2 LC droplets, and decreases aggregation of hnRNPA2 disease variants. Transport granule components hnRNPF and ch-TOG interact weakly with hnRNPA2 but partition specifically into LC droplets. Expression of Fyn kinase in C. elegans reduces neurodegeneration associated with chimeric hnRNPA2 D290V.","method":"In vitro phase separation assays, tyrosine phosphorylation assays, C. elegans neurodegeneration model with Fyn expression, NMR","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro phosphorylation with phase separation assays, in vivo C. elegans rescue, multiple orthogonal methods","pmids":["33349959"],"is_preprint":false},{"year":2016,"finding":"Drosophila model expressing disease-homologous hnRNPA2B1 mutations (Hrb98DE) in fly muscle causes progressive cytoplasmic inclusion pathology containing stress granule marker ROX8 and additional RNA-binding proteins including TDP-43. Overexpression of DNAJB6/MRJ rescues inclusion formation and prevents RBP aggregation after heat shock through a physical interaction; wild-type but not disease-mutant MRJ interacted with RBPs after heat shock.","method":"Drosophila genetic model with disease-homologous mutations, immunofluorescence for inclusions, genetic epistasis (MRJ overexpression/KO), co-immunoprecipitation after heat shock","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in Drosophila model with physical interaction data, disease mutation comparison, multiple orthogonal validations","pmids":["26744327"],"is_preprint":false},{"year":2022,"finding":"Heterozygous frameshift variants in HNRNPA2B1 that extend the reading frame with a novel neomorphic C-terminal sequence (escaping NMD and translated) have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and animal models, causing early-onset oculopharyngeal muscular dystrophy.","method":"Frameshift variant characterization, nuclear import receptor binding assay (karyopherin β2), cellular localization by immunofluorescence, animal models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay with karyopherin β2, localization experiments with functional consequence, 10 independent families and animal model validation","pmids":["35484142"],"is_preprint":false},{"year":2023,"finding":"SUMOylated HNRNPA2B1 (HNRNPA2B1SUMO) acts as an endogenous inhibitor of RPA during normal DNA replication. HNRNPA2B1SUMO associates with RPA through recognizing the SUMO-interacting motif (SIM) of RPA, inhibiting RPA accumulation at replication forks and impeding local ATR activation. DNA damage reduces HNRNPA2B1SUMO, releasing nuclear soluble RPA to chromatin and enabling ATR activation. HNRNPA2B1 hinders homologous recombination repair by limiting RPA availability.","method":"Co-IP identifying SIM-mediated interaction, chromatin fractionation, ATR activation assays, HR repair assays, PARP inhibitor sensitivity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined molecular mechanism (SUMO-SIM interaction), multiple functional readouts (ATR activation, HR, PARP inhibitor sensitivity), single rigorous study","pmids":["36702126"],"is_preprint":false},{"year":2020,"finding":"Solution NMR showed that the two RRMs of hnRNPA2 move independently in solution without RNA. hnRNPA2 RRMs bind the minimal A2RE11 RNA weakly, with NMR shifts in both RRMs upon binding. Short A2RE RNAs or longer RNAs containing this sequence completely prevent in vitro phase separation of full-length hnRNPA2 and aggregation of disease-associated mutants.","method":"Solution NMR spectroscopy, biophysical RNA binding assays, in vitro phase separation assays with RNA addition","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization of RRM-RNA interaction combined with phase separation functional assays, single lab with multiple orthogonal methods","pmids":["32870271"],"is_preprint":false},{"year":2011,"finding":"In pancreatic cancer cells, inhibition of Fyn kinase activity downregulated hnRNPA2B1 expression. hnRNPA2B1 binds Bcl-x mRNA and affects its splicing, promoting formation of anti-apoptotic Bcl-xL (downregulation of hnRNPA2B1 increased pro-apoptotic Bcl-xS formation and apoptosis). Overexpression of hnRNPA2B1 rescued cells from apoptosis.","method":"Kinase-dead Fyn expression, RNA interference knockdown, Bcl-x splicing assay by RT-PCR, apoptosis assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined splicing target (Bcl-x mRNA), functional rescue by overexpression, single lab","pmids":["21642356"],"is_preprint":false},{"year":2010,"finding":"Under mitochondrial respiratory stress, Akt1 phosphorylates hnRNPA2, and this phosphorylation is a crucial step for recruitment of hnRNPA2 as a transcriptional coactivator to stress target promoters (including NFκB/cRel:p50, C/EBPδ, CREB, NFAT pathways), culminating in transcription activation of nuclear genes including Cathepsin L, RyR1, Glut4 and Akt1.","method":"In vivo phosphorylation assays, chromatin immunoprecipitation at stress target promoters, transcription activation assays with dominant-negative constructs","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation established with ChIP showing promoter recruitment, functional outcome measured, single lab","pmids":["20153290"],"is_preprint":false},{"year":2015,"finding":"hnRNPA2/B1 binds the COX-2 core promoter to activate COX-2 expression in non-small-cell lung cancer. hnRNPA2/B1 interacts directly with the transcriptional co-activator p300, which acetylates hnRNPA2/B1. Acetylation by p300 (requiring its HAT domain) enhances hnRNPA2/B1 binding to the COX-2 promoter and promotes COX-2 expression and tumor growth.","method":"ChIP (promoter binding), Co-IP (hnRNPA2B1-p300 interaction), acetylation assays with p300 HAT domain deletion mutant, shRNA/siRNA knockdown with functional readouts","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with mutagenesis of HAT domain, single lab","pmids":["26774881"],"is_preprint":false},{"year":2018,"finding":"hnRNPA2 functions as a lysine acetyltransferase (KAT) that acetylates histone H4 at lysine 8 (H4K8) at telomeres under mitochondrial dysfunction. This H4K8 acetylation is associated with telomere attrition. Expression of a KAT-mutant hnRNPA2 rescued telomere length, suggesting impaired H4K8 acetylation is responsible.","method":"KAT activity assay, histone acetylation assay (H4K8), telomere length measurement, KAT-mutant hnRNPA2 expression rescue","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity established with mutagenesis rescue, single lab, single study","pmids":["30427907"],"is_preprint":false},{"year":2019,"finding":"hnRNPA2B1 binds the 3'-UTR of HIF-1α mRNA through its C-terminal glycine-rich domain, promoting HIF-1α translation. The small molecule MO-460 inhibits initiation of HIF-1α translation by binding to the C-terminal glycine-rich domain of hnRNPA2B1 and blocking its binding to HIF-1α mRNA 3'-UTR.","method":"RNA immunoprecipitation showing hnRNPA2B1-HIF-1α mRNA 3'UTR interaction, chemical proteomics identifying MO-460 binding site, translation assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP binding assay with domain mapping, small molecule disruption of function, single lab","pmids":["30755586"],"is_preprint":false},{"year":2019,"finding":"M1 muscarinic receptor signaling controls hnRNPA2/B1 protein levels by regulating mRNA translation via nonsense-mediated decay regulation, not by altering mRNA levels, protein aggregation, or degradation. Genetic mouse models with decreased or increased cholinergic tone show corresponding changes in hnRNPA2/B1 protein levels.","method":"Genetic mouse models (cholinergic tone manipulation), M1 muscarinic receptor knockout, translation assays, NMD pathway analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse models with defined receptor pathway, translational mechanism established, single lab","pmids":["27277805"],"is_preprint":false},{"year":2019,"finding":"hnRNPA2/B1 localization shifts from nucleus to cytoplasm during mammalian embryonic development, regulated by METTL3-dependent m6A RNA methylation. METTL3 KD blastocysts show increased mislocalization of hnRNPA2/B1, and hnRNPA2/B1 KD causes developmental arrest after the 4-cell stage with decreased OCT4 and SOX2 inner cell mass markers.","method":"Immunofluorescence localization in embryos, hnRNPA2/B1 and METTL3 knockdown with developmental readout, RNA-seq in KD blastocysts","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional developmental consequences, METTL3-hnRNPA2B1 epistasis established, single lab","pmids":["31201338"],"is_preprint":false},{"year":2020,"finding":"In uninfected HEp-2 cells, hnRNPA2B1 is localized in the nucleus and is not a component of exosomes. Upon HSV-1 infection, hnRNPA2B1 is quantitatively exported to the cytoplasm where a fraction colocalizes with a Golgi marker. In ΔhnRNPA2B1 cells, there is a >10-fold reduction in HSV-1 released through the apical surface, but no significant impact on basolateral cell-to-cell transfer.","method":"Subcellular fractionation, immunofluorescence colocalization with Golgi marker, hnRNPA2B1 knockout cells, viral yield quantification","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (viral egress), knockout with specific directional readout, single lab","pmids":["32295924"],"is_preprint":false},{"year":2020,"finding":"Epirubicin disrupts the interaction between hnRNPA2B1 and miR-503 in endothelial cells, leading to hnRNPA2B1 relocalization to the nucleus while miR-503 and ANXA2 are sorted into exosomes. hnRNPA2B1 negatively regulates exosomal sorting of miR-503, establishing that RNA-binding proteins can inhibit exosomal miRNA export.","method":"Biotinylated miR-503 pulldown with mass spectrometry identification, western blotting validation, knockdown systems with pulldown analysis, localization assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown validated by MS and western blot, knockdown with specific sorting readout, single lab","pmids":["31894362"],"is_preprint":false},{"year":2024,"finding":"hnRNPA2B1 is associated with stress granules (SGs) and represses their disassembly. hnRNPA2B1 absence specifically enhances arsenite-induced SG disassembly via the ubiquitin-proteasome system (not autophagy). hnRNPA2B1 interacts with core SG proteins G3BP1, G3BP2, USP10, and Caprin-1; its depletion reduces the G3BP1-USP10/Caprin-1 interaction and elevates G3BP1 ubiquitination. Hnrnpa2b1 KO in mice causes Sertoli cell-only syndrome and complete male infertility.","method":"Co-IP identifying SG protein interactions, ubiquitination assays, proteasome inhibitor experiments, autophagy inhibitor experiments, Hnrnpa2b1 KO mouse model with fertility phenotype","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods identifying specific interactions and mechanism (USP10/G3BP1/ubiquitination axis), in vivo KO model with defined phenotype","pmids":["38363675"],"is_preprint":false},{"year":2022,"finding":"In PAH pulmonary arterial smooth muscle cells, hnRNPA2B1 expression and nuclear localization are increased. hnRNPA2B1 promotes expression of mRNAs carrying three defined binding motifs involved in different aspects of the cell cycle. RNA immunoprecipitation confirmed binding to target mRNAs. hnRNPA2B1 silencing decreased target mRNA levels and reduced proliferation and resistance to apoptosis in PAH-PASMC. In vivo hnRNPA2B1 inhibition in lungs rescued pulmonary hypertension in rats.","method":"RNA immunoprecipitation, bioinformatics motif analysis, hnRNPA2B1 silencing with proliferation/apoptosis readouts, immunofluorescence localization, monocrotaline rat model","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP validation of targets, localization experiment with functional consequence, in vivo rescue, single lab","pmids":["35993245"],"is_preprint":false},{"year":2024,"finding":"hnRNPA2B1 mediates nuclear export of m6A-tagged mRNAs through the ALYREF/NXF1 complex. ISGylation of hnRNPA2B1 (mediated by PCAT6 serving as scaffold between ISG15 and hnRNPA2B1) protects hnRNPA2B1 from ubiquitination-mediated proteasomal degradation, enhancing its ability to selectively export m6A-modified mRNAs.","method":"Co-IP (PCAT6-ISG15-hnRNPA2B1 complex, hnRNPA2B1-ALYREF/NXF1), ISGylation assay, ubiquitination assay, nuclear mRNA export assay, hnRNPA2B1 knockdown","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP interactions establishing a complex, PTM (ISGylation) protecting from ubiquitination, mRNA export functional assay, single lab","pmids":["38626369"],"is_preprint":false},{"year":2022,"finding":"hnRNPA2B1 mediates microRNA processing (specifically miR-92a-2-5p and miR-373-3p) via interaction with DGCR8 (confirmed by Co-IP). These processed miRNAs are transported in exosomes to recipient monocytes or mesenchymal stem cells to activate osteoclastogenesis and suppress osteoblastogenesis by inhibiting IRF8 or RUNX2.","method":"RNA pull-down, RIP assays for hnRNPA2B1-pri-miRNA interaction, Co-IP for hnRNPA2B1-DGCR8, exosome isolation and characterization, luciferase assay for miRNA targets","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down and RIP validated, Co-IP for DGCR8, functional downstream assays, single lab","pmids":["36451863"],"is_preprint":false},{"year":2020,"finding":"HNRNPA2B1 interacts with KRAS mRNA and facilitates its nuclear export and translation in colorectal cancer. The lncRNA CRNDE maintains HNRNPA2B1 protein stability by inhibiting E3 ubiquitin ligase TRIM21-mediated K63 ubiquitination-dependent degradation. The CRNDE/hnRNPA2B1 axis activates MAPK signaling through KRAS.","method":"RNA immunoprecipitation for KRAS mRNA binding, nuclear export assay, ubiquitination assay identifying TRIM21 as E3 ligase, Co-IP, CRISPR KO experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, ubiquitination mechanism defined, nuclear export functional assay, single lab","pmids":["37716979"],"is_preprint":false},{"year":2020,"finding":"Linc01232 physically interacts with the RNA recognition motif 2 domain of HNRNPA2B1 (680-890 nt fragment) and inhibits its ubiquitin-mediated degradation, stabilizing HNRNPA2B1. Stabilized HNRNPA2B1 participates in alternative splicing of A-Raf, regulating the MAPK/ERK signaling pathway.","method":"RNA pull-down, RIP assays, domain mapping of HNRNPA2B1 interaction region, ubiquitination assays, RNA-seq for alternative splicing","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down with domain mapping, ubiquitination assay, splicing outcome measured, single lab","pmids":["32814086"],"is_preprint":false},{"year":2022,"finding":"hnRNPA2/B1 regulates copper homeostasis by modulating the abundance of Cu(I)-transporter ATP7A via the 3' UTR of the ATP7A transcript in an isoform-dependent manner. Downregulation of B1 and B1b isoforms is sufficient to elevate ATP7A, while overexpression of either hnRNPA2 or hnRNPB1 isoforms decreases ATP7A mRNA levels.","method":"siRNA knockdown of specific isoforms, isoform-specific overexpression, 3'UTR reporter assay, mRNA and protein quantification, copper level measurement","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific functional dissection with 3'UTR mechanistic link, multiple isoform conditions tested, single lab","pmids":["36545508"],"is_preprint":false},{"year":2025,"finding":"hnRNPA2B1 is a sensor for the metabolite adenine in the nucleus. Adenine directly binds and activates hnRNPA2B1, which is then recruited to Il1b enhancers. hnRNPA2B1 increases Il1b enhancer chromatin accessibility by binding and recruiting nucleolin and the demethylase FTO to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation, thereby increasing IL-1β production during bacterial infection.","method":"Large-scale metabolite-hnRNPA2B1 interaction screen, direct binding assay (adenine-hnRNPA2B1), ChIP at Il1b enhancers, chromatin accessibility assay, Co-IP with nucleolin and FTO, myeloid-specific cKO mice with bacterial infection","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding screen, ChIP, chromatin accessibility, Co-IP with specific recruiters, in vivo cKO model with rescue by IL-1β, multiple orthogonal methods","pmids":["39814017"],"is_preprint":false},{"year":2022,"finding":"A hnRNPA2B1 agonist compound PAC5 binds near Asp49 in the RNA recognition motif of hnRNPA2B1, activating it and promoting its translocation to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to type I IFN production with antiviral activity against HBV and SARS-CoV-2.","method":"Binding site characterization by structural analysis (near Asp49 in RRM), nuclear-cytoplasmic fractionation, TBK1-IRF3 activation assay, in vivo HBV and hamster SARS-CoV-2 models","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding site defined, translocation with functional consequence, in vivo efficacy, single lab","pmids":["36726760"],"is_preprint":false},{"year":2024,"finding":"hnRNPA2B1 stabilizes SREBP2 mRNA via m6A modification and similarly stabilizes LDLR mRNA in an m6A-dependent manner, triggering de novo cholesterol synthesis through HMGCR induction and promoting glioma stemness.","method":"RNA immunoprecipitation for SREBP2/LDLR mRNA binding, m6A MeRIP sequencing, RNA stability assay, hnRNPA2B1 ablation with transcriptome and lipidomic readouts","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and MeRIP defining m6A-dependent binding, RNA stability assay, single lab","pmids":["38070488"],"is_preprint":false},{"year":2017,"finding":"HNRNPA2B1 mediates exclusion of cassette exon 11 from MST1R pre-mRNA (validated by minigene model), generating the RON∆165 isoform that activates Akt/PKB signaling in head and neck cancer. Depletion of HNRNPA2B1 by CRISPR/Cas9 causes exon 11 inclusion, reducing RON∆165 and inhibiting Akt/PKB signaling, leading to reduced EMT.","method":"CRISPR/Cas9 knockout, MST1R-minigene splicing assay, isoform-specific RT-PCR, Akt/PKB signaling assays","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene validation of specific exon skipping, CRISPR KO with pathway readout, single lab","pmids":["32669614"],"is_preprint":false},{"year":2017,"finding":"Nm23-H1 increases the protein stability of hnRNPA2/B1 and both are co-recruited to the 5'UTR of Sp1 mRNA to regulate its cap-independent (IRES-mediated) translational activity in lung cancer cells.","method":"Co-IP of Nm23-H1 and hnRNPA2/B1, RNA immunoprecipitation of 5'UTR of Sp1 mRNA, IRES-based reporter assay, protein stability assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RIP of mRNA 5'UTR, IRES reporter functional assay, single lab","pmids":["28831131"],"is_preprint":false},{"year":2014,"finding":"hnRNP-A2/B1 binds directly to the ASCL1 mRNA 5'- and 3'-UTRs (identified by RNA pulldown and MALDI/TOF-MS) and functions as a key positive regulator of ASCL1 expression. Downregulation of hnRNP-A2/B1 during hypoxia is associated with post-transcriptional suppression of hASH1 synthesis.","method":"RNA pulldown with MALDI/TOF-MS identification, reporter gene assays for 5'- and 3'-UTR function, siRNA knockdown, hypoxia exposure","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown with MS identification, reporter assays for UTR function, single lab","pmids":["25124043"],"is_preprint":false},{"year":2023,"finding":"CSNK1D (casein kinase 1 delta) phosphorylates HNRNPA2B1 to enhance its stability. Phosphorylated/stabilized HNRNPA2B1 promotes maturation of miR-25-3p and miR-93-5p by recognizing m6A marks on primary miR-25/93 transcripts. miR-93-5p targets BAMBI to activate TGF-β pathway; miR-25-3p targets FOXO3 to inactivate FOXO pathway.","method":"Mass spectrometry identifying CSNK1D as kinase, phosphorylation and stability assays, m6A RIP for pri-miRNA binding, pri-miRNA processing assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of kinase, PTM stability mechanism, m6A-dependent pri-miRNA processing, single lab","pmids":["37208565"],"is_preprint":false},{"year":2013,"finding":"PARP1 and HNRNPA2B1 specifically bind DNA sequences at the termini of 'forum domains' — chromosomal regions of 50-250 kb flanked by DNA double-strand break hot spots that contain coordinately expressed genes, suggesting a structural role in coordinated transcription of gene clusters.","method":"Genome-wide mapping of blunt-ended DSBs, ChIP-seq for PARP1 and HNRNPA2B1 binding at domain termini","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-seq binding data establishing genomic localization, single lab, no functional perturbation","pmids":["23593027"],"is_preprint":false},{"year":2024,"finding":"hnRNPA2B1 interacts with PABPC1, and this complex coordinates with the cap-binding eIF4F complex to facilitate translation of CIP2A, DLAT, and GPX1 mRNAs independent of m6A modification in gastric cancer cells. H. pylori infection induces hnRNPA2B1 upregulation through NF-κB recruitment to its promoter.","method":"Mass spectrometry and Co-IP for hnRNPA2B1-PABPC1 interaction, Ribo-seq and polysome profiling for translational regulation, RIP-seq for mRNA targets, m6A epitranscriptomic microarray","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP validated by MS, polysome profiling for translation, m6A microarray distinguishing m6A-independent mechanism, single lab","pmids":["38887155"],"is_preprint":false}],"current_model":"HNRNPA2B1 is a multifunctional RNA-binding protein that acts as a nuclear m6A reader (binding m6A-modified RNAs via its RRM domains), promotes primary miRNA processing by interacting with the DGCR8 Microprocessor complex, regulates alternative splicing and polyadenylation of thousands of transcripts, controls miRNA sorting into exosomes through sumoylation-regulated EXO-motif recognition, senses viral and bacterial-derived nucleic acids/metabolites to trigger innate immune signaling via TBK1-IRF3 after JMJD6-mediated demethylation and cytoplasmic translocation, forms functional liquid-liquid phase-separated granules through its intrinsically disordered low-complexity domain whose pathogenic mutations (e.g., D290V) stabilize amyloid-like fibrils causing multisystem proteinopathy, acts as a transcriptional coactivator upon Akt1-mediated phosphorylation during mitochondrial stress, represses stress granule disassembly by stabilizing the G3BP1-USP10/Caprin-1 interaction, inhibits RPA accumulation at replication forks in its SUMOylated form to regulate ATR activation and DNA repair, and is regulated by multiple post-translational modifications including sumoylation, arginine methylation (by PRMT), tyrosine phosphorylation (by Fyn), acetylation (by p300), and ubiquitination (by TRIM21/FBXO11)."},"narrative":{"mechanistic_narrative":"HNRNPA2B1 is a multifunctional, modification-regulated RNA-binding protein that couples RNA metabolism to gene expression, genome maintenance, innate immunity, and proteostasis [PMID:26321680, PMID:27773581]. In the nucleus it acts as a reader of N6-methyladenosine, binding m6A-marked transcripts through its RRM domains to direct alternative splicing, promote Microprocessor-dependent primary miRNA processing via interaction with DGCR8, and mediate nuclear export of m6A-tagged mRNAs through the ALYREF/NXF1 pathway [PMID:26321680, PMID:38626369]. Genome-wide it binds UAGG-containing sites in thousands of transcripts and governs alternative splicing and polyadenylation, including disease-relevant targets in motor neurons [PMID:27773581]. Its intrinsically disordered low-complexity (prion-like) domain drives liquid–liquid phase separation and assembly of stress-granule-associated, amyloid-like cross-β polymers; pathogenic mutations in this domain (e.g., D290V, P298L) strengthen a steric zipper, stabilize self-seeding fibrils, and drive cytoplasmic inclusion formation, while RNA binding and arginine methylation oppose phase separation [PMID:23455423, PMID:29358076, PMID:32796831, PMID:32870271]. Heterozygous PrLD missense mutations and reading-frame-extending frameshift variants that impair karyopherin-β2 binding cause multisystem proteinopathy and early-onset oculopharyngeal muscular dystrophy, respectively [PMID:23455423, PMID:35484142]. HNRNPA2B1 stabilizes stress granules by maintaining the G3BP1–USP10/Caprin-1 interaction, and Hnrnpa2b1 loss in mice causes Sertoli-cell-only syndrome and male infertility [PMID:38363675]. It functions as a nucleic-acid and metabolite sensor in innate immunity: it senses viral DNA, homodimerizes, and after JMJD6-mediated arginine demethylation translocates to the cytoplasm to activate TBK1-IRF3 and type I IFN production, and it senses nuclear adenine to remodel Il1b enhancer chromatin via nucleolin and FTO [PMID:31320558, PMID:39814017]. Its activity is tuned by an extensive set of post-translational modifications—sumoylation, arginine methylation, tyrosine phosphorylation by Fyn, acetylation by p300, ISGylation, and ubiquitination by TRIM21—that control its localization, stability, phase behavior, and substrate selection [PMID:24356509, PMID:31320558, PMID:33349959, PMID:36702126, PMID:38626369, PMID:37716979]. SUMOylated HNRNPA2B1 additionally restrains RPA accumulation at replication forks to limit ATR activation and homologous recombination repair [PMID:36702126].","teleology":[{"year":2010,"claim":"Established that HNRNPA2 acts beyond RNA metabolism as a stress-responsive transcriptional coactivator, linking mitochondrial stress signaling to nuclear gene transcription.","evidence":"In vivo phosphorylation assays and ChIP at stress target promoters with dominant-negative constructs under mitochondrial respiratory stress","pmids":["20153290"],"confidence":"Medium","gaps":["Direct vs. indirect promoter binding not structurally resolved","Generality beyond the specific stress promoters tested unclear"]},{"year":2013,"claim":"Defined the prion-like domain as the structural basis of disease, showing PrLD mutations strengthen a steric zipper to drive self-seeding fibrils and cytoplasmic inclusions.","evidence":"Fibril assembly and seeding assays, stress granule imaging in cells and animal models, mutagenesis","pmids":["23455423"],"confidence":"High","gaps":["Atomic fibril architecture not yet resolved at this stage","In vivo trigger of pathological transition not defined"]},{"year":2013,"claim":"Identified HNRNPA2B1 as the RNA-binding protein controlling sequence-specific loading of miRNAs into exosomes, regulated by sumoylation.","evidence":"RNA immunoprecipitation, sumoylation assays, and EXO-motif mutagenesis with exosomal miRNA readout","pmids":["24356509"],"confidence":"High","gaps":["SUMO site and machinery not fully mapped","Mechanism coupling sumoylation to RNA affinity unresolved"]},{"year":2015,"claim":"Established HNRNPA2B1 as a nuclear m6A reader that couples the mark to alternative splicing and Microprocessor-dependent pri-miRNA processing via DGCR8.","evidence":"In vitro and in vivo RIP, splicing assays, METTL3/HNRNPA2B1 knockdown epistasis, and Co-IP with DGCR8","pmids":["26321680"],"confidence":"High","gaps":["Direct m6A contact vs. structural remodeling debated","Selectivity rules for which m6A transcripts are read not defined"]},{"year":2015,"claim":"Showed the LC domain adopts the same cross-β polymeric conformation in hydrogels, droplets, and native nuclei, arguing for a physiological role of LC polymerization.","evidence":"Molecular footprinting of LC polymeric state, hydrogel preparation, EM, and analysis of isolated nuclei","pmids":["26544936"],"confidence":"High","gaps":["Functional readout of nuclear polymerization not directly measured","Reversibility in vivo not quantified"]},{"year":2016,"claim":"Mapped transcriptome-wide binding (UAGG motifs) and a role in alternative polyadenylation and splicing, connecting loss of function and the D290V mutant to ALS-relevant mis-splicing.","evidence":"CLIP-seq in mouse spinal cord, RNA-seq upon knockdown, and patient fibroblast/iPSC-motor neuron analysis","pmids":["27773581"],"confidence":"High","gaps":["Causal contribution of individual splicing targets to disease unproven","Mechanism linking insolubility to splicing defects unclear"]},{"year":2018,"claim":"Provided structural insight into LC-domain disorder and phase separation, and showed arginine methylation suppresses phase separation while disease mutations enhance aggregation.","evidence":"NMR spectroscopy, in vitro phase separation and arginine methylation assays, mutagenesis","pmids":["29358076","30279180"],"confidence":"High","gaps":["Endogenous methylation stoichiometry not measured","Cross-seeding of TDP-43 in vivo not established"]},{"year":2018,"claim":"Demonstrated regulation of phase behavior by Fyn-SH3 binding to the LC domain, defining a kinase–client interface controlling granule assembly.","evidence":"Solution NMR and in vitro phase separation microscopy","pmids":["30397184"],"confidence":"High","gaps":["Cellular consequence of Fyn-SH3 recruitment not measured here","Stoichiometry in physiological granules unknown"]},{"year":2019,"claim":"Revealed HNRNPA2B1 as a nuclear viral-DNA sensor that, after JMJD6-mediated arginine demethylation, translocates to the cytoplasm to drive TBK1-IRF3 type I IFN signaling.","evidence":"Co-IP, JMJD6 demethylation assays, nuclear-cytoplasmic fractionation, TBK1-IRF3 activation, and m6A RIP on CGAS/IFI16/STING mRNAs","pmids":["31320558"],"confidence":"High","gaps":["Direct DNA-binding mode not structurally resolved","How demethylation triggers nuclear export mechanistically unclear"]},{"year":2020,"claim":"Resolved wild-type vs. D290V fibril architecture at atomic resolution, explaining how the mutation thermodynamically stabilizes pathogenic polymers.","evidence":"CryoEM of the LCD fibril core, crystal structure of the D290V segment, and energetic calculations","pmids":["32796831"],"confidence":"High","gaps":["Relationship between in vitro fibril and in vivo inclusion structure not established","Therapeutic targetability of the zipper untested"]},{"year":2020,"claim":"Showed RRM-bound A2RE RNA suppresses phase separation and aggregation, establishing RNA as a built-in regulator of HNRNPA2B1 condensation.","evidence":"Solution NMR of RRM–RNA interaction and in vitro phase separation assays with RNA addition","pmids":["32870271"],"confidence":"High","gaps":["RNA concentrations relevant in vivo not defined","Whether endogenous RNAs protect cells from aggregation untested"]},{"year":2020,"claim":"Demonstrated Fyn tyrosine phosphorylation reduces phase separation and disease-variant aggregation and rescues neurodegeneration in vivo.","evidence":"In vitro tyrosine phosphorylation and phase separation assays plus C. elegans Fyn-expression rescue","pmids":["33349959"],"confidence":"High","gaps":["Mammalian in vivo phosphorylation dynamics not measured","Phosphosite occupancy under stress unknown"]},{"year":2023,"claim":"Identified a non-canonical genome-protective role: SUMOylated HNRNPA2B1 sequesters RPA via its SIM to limit fork RPA loading and ATR activation, tuning DNA repair.","evidence":"Co-IP defining SUMO-SIM interaction, chromatin fractionation, ATR activation, HR assays, and PARP inhibitor sensitivity","pmids":["36702126"],"confidence":"High","gaps":["SUMO E3 ligase responsible not identified","Crosstalk with HNRNPA2B1's RNA functions during replication stress unclear"]},{"year":2024,"claim":"Defined HNRNPA2B1 as a repressor of stress-granule disassembly through the G3BP1-USP10/Caprin-1 axis and as essential for spermatogenesis in vivo.","evidence":"Co-IP, ubiquitination and proteasome/autophagy inhibitor assays, and Hnrnpa2b1 KO mouse fertility phenotyping","pmids":["38363675"],"confidence":"High","gaps":["Direct vs. scaffold role in the G3BP1 complex unresolved","Link between SG regulation and the infertility phenotype not established"]},{"year":2024,"claim":"Linked ISGylation to control of HNRNPA2B1 stability and selective m6A-mRNA nuclear export via ALYREF/NXF1.","evidence":"Co-IP of PCAT6-ISG15-HNRNPA2B1 and HNRNPA2B1-ALYREF/NXF1, ISGylation and ubiquitination assays, and mRNA export assays","pmids":["38626369"],"confidence":"Medium","gaps":["ISGylation site not mapped","Competition between ISGylation and ubiquitination not quantified"]},{"year":2025,"claim":"Extended HNRNPA2B1's sensor function to a small metabolite, showing nuclear adenine binding activates it to remodel Il1b enhancer chromatin and drive IL-1β during bacterial infection.","evidence":"Metabolite-protein interaction screen, direct adenine binding, ChIP and chromatin accessibility at Il1b enhancers, Co-IP with nucleolin/FTO, and myeloid cKO mice","pmids":["39814017"],"confidence":"High","gaps":["Adenine-binding pocket structure not resolved","Generality to other metabolites and enhancers untested"]},{"year":null,"claim":"How HNRNPA2B1's many post-translational modifications are integrated to switch it between its nuclear RNA-processing, condensate, genome-protective, and cytoplasmic immune-sensing states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating SUMO/methyl/phospho/acetyl/ISG/ubiquitin marks","Quantitative partitioning between competing functions in a single cell unknown","Structural basis for RRM-mediated nucleic-acid and metabolite sensing incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,6,16,21,27,35,38]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,29,39]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,33,40]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[18,19,33]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[20]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,33]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,15,24,40]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,23,24,34]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[33]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,25,29]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,6,28,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,33,34]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[15]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[18,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[18,19,33]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[28,30]}],"complexes":["Microprocessor (with DGCR8)","stress granule (G3BP1/USP10/Caprin-1)","ALYREF/NXF1 mRNA export complex"],"partners":["DGCR8","JMJD6","G3BP1","USP10","CAPRIN-1","PABPC1","TRIM21","FYN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22626","full_name":"Heterogeneous nuclear ribonucleoproteins A2/B1","aliases":[],"length_aa":353,"mass_kda":37.4,"function":"Heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with nascent pre-mRNAs, packaging them into hnRNP particles. The hnRNP particle arrangement on nascent hnRNA is non-random and sequence-dependent and serves to condense and stabilize the transcripts and minimize tangling and knotting. Packaging plays a role in various processes such as transcription, pre-mRNA processing, RNA nuclear export, subcellular location, mRNA translation and stability of mature mRNAs (PubMed:19099192). Forms hnRNP particles with at least 20 other different hnRNP and heterogeneous nuclear RNA in the nucleus. Involved in transport of specific mRNAs to the cytoplasm in oligodendrocytes and neurons: acts by specifically recognizing and binding the A2RE (21 nucleotide hnRNP A2 response element) or the A2RE11 (derivative 11 nucleotide oligonucleotide) sequence motifs present on some mRNAs, and promotes their transport to the cytoplasm (PubMed:10567417). Specifically binds single-stranded telomeric DNA sequences, protecting telomeric DNA repeat against endonuclease digestion (By similarity). Also binds other RNA molecules, such as primary miRNA (pri-miRNAs): acts as a nuclear 'reader' of the N6-methyladenosine (m6A) mark by specifically recognizing and binding a subset of nuclear m6A-containing pri-miRNAs. Binding to m6A-containing pri-miRNAs promotes pri-miRNA processing by enhancing binding of DGCR8 to pri-miRNA transcripts (PubMed:26321680). Involved in miRNA sorting into exosomes following sumoylation, possibly by binding (m6A)-containing pre-miRNAs (PubMed:24356509). Acts as a regulator of efficiency of mRNA splicing, possibly by binding to m6A-containing pre-mRNAs (PubMed:26321680). Plays a role in the splicing of pyruvate kinase PKM by binding repressively to sequences flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (PubMed:20010808). Also plays a role in the activation of the innate immune response (PubMed:31320558). Mechanistically, senses the presence of viral DNA in the nucleus, homodimerizes and is demethylated by JMJD6 (PubMed:31320558). In turn, translocates to the cytoplasm where it activates the TBK1-IRF3 pathway, leading to interferon alpha/beta production (PubMed:31320558) (Microbial infection) Involved in the transport of HIV-1 genomic RNA out of the nucleus, to the microtubule organizing center (MTOC), and then from the MTOC to the cytoplasm: acts by specifically recognizing and binding the A2RE (21 nucleotide hnRNP A2 response element) sequence motifs present on HIV-1 genomic RNA, and promotes its transport","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P22626/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPA2B1","classification":"Not Classified","n_dependent_lines":427,"n_total_lines":1208,"dependency_fraction":0.353476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":10.0},{"gene":"HNRNPL","stoichiometry":10.0},{"gene":"HNRNPC","stoichiometry":10.0},{"gene":"RBMX","stoichiometry":10.0},{"gene":"TOP1","stoichiometry":10.0},{"gene":"DDX5","stoichiometry":4.0},{"gene":"ILF3","stoichiometry":4.0},{"gene":"HNRNPH1","stoichiometry":4.0},{"gene":"IGF2BP1","stoichiometry":4.0},{"gene":"RBM14","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPA2B1","total_profiled":1310},"omim":[{"mim_id":"620460","title":"OCULOPHARYNGEAL MUSCULAR DYSTROPHY 2; OPMD2","url":"https://www.omim.org/entry/620460"},{"mim_id":"620030","title":"ARGININE- AND SERINE-RICH PROTEIN 1; RSRP1","url":"https://www.omim.org/entry/620030"},{"mim_id":"619854","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, IMPAIRED SPEECH, AND BEHAVIORAL ABNORMALITIES; NEDHISB","url":"https://www.omim.org/entry/619854"},{"mim_id":"617549","title":"TUMOR PROTEIN p53-INDUCIBLE NUCLEAR PROTEIN 2; TP53INP2","url":"https://www.omim.org/entry/617549"},{"mim_id":"617158","title":"MYOPATHY, DISTAL, WITH RIMMED VACUOLES; DMRV","url":"https://www.omim.org/entry/617158"}],"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/HNRNPA2B1"},"hgnc":{"alias_symbol":["HNRNPA2","HNRNPB1"],"prev_symbol":["HNRPA2B1"]},"alphafold":{"accession":"P22626","domains":[{"cath_id":"3.30.70.330","chopping":"17-96","consensus_level":"high","plddt":95.971,"start":17,"end":96},{"cath_id":"3.30.70.330","chopping":"112-197","consensus_level":"high","plddt":91.9791,"start":112,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22626","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22626-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22626-F1-predicted_aligned_error_v6.png","plddt_mean":69.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPA2B1","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPA2B1"},"sequence":{"accession":"P22626","fasta_url":"https://rest.uniprot.org/uniprotkb/P22626.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22626/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22626"}},"corpus_meta":[{"pmid":"24356509","id":"PMC_24356509","title":"Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24356509","citation_count":1620,"is_preprint":false},{"pmid":"26321680","id":"PMC_26321680","title":"HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26321680","citation_count":1278,"is_preprint":false},{"pmid":"23455423","id":"PMC_23455423","title":"Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23455423","citation_count":1225,"is_preprint":false},{"pmid":"29358076","id":"PMC_29358076","title":"Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29358076","citation_count":328,"is_preprint":false},{"pmid":"31320558","id":"PMC_31320558","title":"Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses.","date":"2019","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31320558","citation_count":309,"is_preprint":false},{"pmid":"26544936","id":"PMC_26544936","title":"The LC Domain of hnRNPA2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-like Droplets, and Nuclei.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26544936","citation_count":245,"is_preprint":false},{"pmid":"34453888","id":"PMC_34453888","title":"Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34453888","citation_count":160,"is_preprint":false},{"pmid":"35279145","id":"PMC_35279145","title":"Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35279145","citation_count":156,"is_preprint":false},{"pmid":"27773581","id":"PMC_27773581","title":"Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/27773581","citation_count":154,"is_preprint":false},{"pmid":"33794982","id":"PMC_33794982","title":"HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33794982","citation_count":131,"is_preprint":false},{"pmid":"32698890","id":"PMC_32698890","title":"Long non-coding RNA H19 promotes colorectal cancer metastasis via binding to hnRNPA2B1.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32698890","citation_count":116,"is_preprint":false},{"pmid":"12906852","id":"PMC_12906852","title":"Transgenes encompassing dual-promoter CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing.","date":"2003","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12906852","citation_count":109,"is_preprint":false},{"pmid":"31263129","id":"PMC_31263129","title":"HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31263129","citation_count":88,"is_preprint":false},{"pmid":"32796831","id":"PMC_32796831","title":"CryoEM structure of the low-complexity domain of hnRNPA2 and its conversion to pathogenic 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38331110","citation_count":12,"is_preprint":false},{"pmid":"26030368","id":"PMC_26030368","title":"Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.","date":"2015","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26030368","citation_count":12,"is_preprint":false},{"pmid":"40103230","id":"PMC_40103230","title":"Small molecule inhibitors of hnRNPA2B1-RNA interactions reveal a predictable sorting of RNA subsets into extracellular vesicles.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40103230","citation_count":11,"is_preprint":false},{"pmid":"25124043","id":"PMC_25124043","title":"Shutdown of achaete-scute homolog-1 expression by heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 in hypoxia.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25124043","citation_count":11,"is_preprint":false},{"pmid":"36545508","id":"PMC_36545508","title":"Heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates the abundance of the copper-transporter ATP7A in an isoform-dependent manner.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36545508","citation_count":10,"is_preprint":false},{"pmid":"36693492","id":"PMC_36693492","title":"m6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer.","date":"2023","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36693492","citation_count":10,"is_preprint":false},{"pmid":"37990246","id":"PMC_37990246","title":"Circular RNA ZBTB46 depletion alleviates the progression of Atherosclerosis by regulating the ubiquitination and degradation of hnRNPA2B1 via the AKT/mTOR pathway.","date":"2023","source":"Immunity & ageing : I & A","url":"https://pubmed.ncbi.nlm.nih.gov/37990246","citation_count":10,"is_preprint":false},{"pmid":"37977260","id":"PMC_37977260","title":"HIF-1α inhibition by MO-2097, a novel chiral-free benzofuran targeting hnRNPA2B1.","date":"2023","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/37977260","citation_count":10,"is_preprint":false},{"pmid":"28542905","id":"PMC_28542905","title":"Perfecting prediction of mutational impact on the aggregation propensity of the ALS-associated hnRNPA2 prion-like protein.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28542905","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55858,"output_tokens":11639,"usd":0.171079,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22597,"output_tokens":5549,"usd":0.125855,"stage2_stop_reason":"end_turn"},"total_usd":0.296934,"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\": 2013,\n      \"finding\": \"hnRNPA2B1 specifically binds exosomal miRNAs through recognition of specific sequence motifs (EXO motifs), controlling their loading into exosomes. In exosomes, hnRNPA2B1 is sumoylated, and sumoylation controls its binding to miRNAs. Mutagenesis of identified motifs or changes in hnRNPA2B1 expression levels modulate miRNA loading into exosomes.\",\n      \"method\": \"RNA immunoprecipitation, sumoylation assays, mutagenesis of miRNA motifs, modulation of hnRNPA2B1 expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, mutagenesis validation, functional rescue, replicated concept across multiple subsequent papers\",\n      \"pmids\": [\"24356509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HNRNPA2B1 binds m6A-bearing RNAs in vivo and in vitro with a biochemical footprint matching the m6A consensus motif, acting as a nuclear reader of the m6A mark. It mediates alternative splicing of nuclear transcripts similarly to the m6A writer METTL3, binds m6A marks in primary miRNA transcripts, interacts with the Microprocessor complex protein DGCR8, and promotes primary miRNA processing.\",\n      \"method\": \"RNA immunoprecipitation (in vivo and in vitro), alternative splicing assays, HNRNPA2B1 and METTL3 knockdown with pri-miRNA processing readout, Co-IP with DGCR8\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, in vivo RIP, parallel KD epistasis, Co-IP), replicated by multiple subsequent studies\",\n      \"pmids\": [\"26321680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pathogenic missense mutations in the prion-like domain (PrLD) of hnRNPA2B1 (e.g., D290V) strengthen a steric zipper motif, exacerbating formation of self-seeding fibrils that cross-seed wild-type hnRNP polymerization. Wild-type hnRNPA2 shows intrinsic tendency to assemble into self-seeding fibrils. Disease mutations promote excess incorporation into stress granules and drive cytoplasmic inclusion formation in animal models.\",\n      \"method\": \"Fibril assembly assays, seeding experiments, stress granule imaging in cells and animal models, mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro fibril reconstitution, mutagenesis, animal model validation, replicated by multiple structural and biophysical studies\",\n      \"pmids\": [\"23455423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer and retains predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending the aggregation-prone region respectively. The hnRNPA2 LC domain directly interacts with and induces phase separation of TDP-43. Arginine methylation reduces hnRNPA2 phase separation by disrupting arginine-mediated contacts.\",\n      \"method\": \"NMR spectroscopy, in vitro phase separation assays, mutagenesis, arginine methylation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural characterization, mutagenesis, in vitro reconstitution of phase separation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"29358076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Upon DNA virus infection, nuclear hnRNPA2B1 senses viral DNA, homodimerizes, and is then demethylated at arginine-226 by the arginine demethylase JMJD6. This leads to hnRNPA2B1 translocation to the cytoplasm where it activates the TBK1-IRF3 pathway, inducing IFN-α/β production. Additionally, hnRNPA2B1 facilitates m6A modification and nucleocytoplasmic trafficking of CGAS, IFI16, and STING mRNAs to amplify cytoplasmic antiviral signaling.\",\n      \"method\": \"Co-IP, demethylation assays identifying JMJD6 as writer/eraser, nuclear-cytoplasmic fractionation, TBK1-IRF3 pathway activation assays, m6A RIP on CGAS/IFI16/STING mRNAs\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods identifying specific PTM writer (JMJD6), localization change with functional consequence (IFN production), mRNA trafficking assays\",\n      \"pmids\": [\"31320558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The LC domain of hnRNPA2 adopts a similar conformation in hydrogel polymers, liquid-like droplets, and isolated nuclei, forming amyloid-like cross-β fibers. A molecular footprinting technique applied to native hnRNPA2 in isolated nuclei showed its LC domain exists in a similar polymeric conformation to recombinant polymers, suggesting biologic utility for LC domain polymerization in information transfer.\",\n      \"method\": \"Molecular footprinting of polymeric LC domain state, hydrogel polymer preparation, electron microscopy, analysis of isolated nuclei\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel footprinting methodology applied both in vitro and to native nuclear protein, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"26544936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transcriptome-wide CLIP in mouse spinal cord identified UAGG motifs enriched within ~2,500 hnRNP A2/B1 binding sites and revealed a role for hnRNP A2/B1 in alternative polyadenylation. hnRNP A2/B1 loss causes alternative splicing changes including skipping of an exon in ALS-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated D290V mutant shows increased nuclear-insoluble hnRNP A2/B1 and abnormal splicing in patient fibroblasts and iPSC-derived motor neurons.\",\n      \"method\": \"CLIP-seq in mouse spinal cord, RNA-seq upon KD, patient fibroblast and iPSC-MN analysis, nuclear fractionation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptome-wide CLIP with defined binding motifs, multiple cell types validated, disease mutation functional comparison\",\n      \"pmids\": [\"27773581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CryoEM structure of the hnRNPA2 LCD fibril core revealed chains kinked in a cross-β conformation enabling non-covalent cross-linking of fibrils, distinguishing them from pathogenic amyloid. The D290V disease mutation fundamentally alters fibril structure to a more stable energetic state, as shown by crystal structure of the D290V-containing segment forming a steric zipper.\",\n      \"method\": \"CryoEM structure determination, crystal structure of D290V segment, hydrogel formation assay, energetic calculations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution cryoEM and crystal structures with direct comparison of wild-type vs. disease mutant fibril architecture\",\n      \"pmids\": [\"32796831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Solid-state NMR with segmental isotope labeling showed that both wild-type hnRNPA2 LC and the D290V mutant form labile polymers in an in-register cross-β conformation. Aspartic acid 290 is charged at physiological pH and immobilized within the polymer core; D290V mutation removes destabilizing electrostatic interactions, making polymers thermodynamically more stable.\",\n      \"method\": \"Solid-state NMR spectroscopy with segmental isotope labeling, electron microscopy, thermodynamic stability measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — solid-state NMR structural characterization with mutagenesis and stability measurements, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30279180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Optogenetically induced tau oligomers (oTau) associate with HNRNPA2B1 (identified by proteomics and validated in neurons, animal models, and human Alzheimer brain). HNRNPA2B1 functions as a linker connecting oTau with m6A-modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau from associating with m6A or reducing protein synthesis and reduces oTau-induced neurodegeneration.\",\n      \"method\": \"Optogenetic tau oligomerization (Cry2-based), proteomics, Co-IP in neurons and animal models, HNRNPA2B1 knockdown with neurodegeneration readout, m6A association assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across multiple model systems including human tissue, functional rescue experiments\",\n      \"pmids\": [\"34453888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HNRNPA2B1 (hnRNP A2 and B1 proteins encoded by HNRNPA2B1) interacts with oncogenic KRAS G12V in PDAC cells as shown by mass spectrometry and Co-IP. This interaction requires KRAS phosphorylation at serine 181. Knockdown of HNRNPA2B1 inactivates AKT-mTOR signaling, reduces interaction between KRAS and PI3K, and reduces KRAS-dependent PDAC cell survival and tumor formation.\",\n      \"method\": \"Mass spectrometry pulldown, Co-IP, Phos-tag phosphorylation analysis, shRNA knockdown, xenograft tumor models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification validated by Co-IP, phosphorylation requirement established, functional consequence in vitro and in vivo, single lab\",\n      \"pmids\": [\"24998203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The SH3 domain of Fyn kinase (Fyn-SH3) interacts with the hnRNPA2 low-complexity domain despite hnRNPA2 lacking canonical SH3-binding sequences. Fyn-SH3 induces hnRNPA2 LC phase separation and is incorporated into in vitro phase-separated granules. NMR identified hnRNPA2 LC interaction sites on the surface of Fyn-SH3.\",\n      \"method\": \"In vitro microscopy, solution NMR spectroscopy, in vitro phase separation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization of interaction combined with in vitro phase separation microscopy, single lab with two orthogonal methods\",\n      \"pmids\": [\"30397184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vitro tyrosine phosphorylation of hnRNPA2 by Fyn reduces hnRNPA2 phase separation, prevents partitioning of hnRNPF and ch-TOG into hnRNPA2 LC droplets, and decreases aggregation of hnRNPA2 disease variants. Transport granule components hnRNPF and ch-TOG interact weakly with hnRNPA2 but partition specifically into LC droplets. Expression of Fyn kinase in C. elegans reduces neurodegeneration associated with chimeric hnRNPA2 D290V.\",\n      \"method\": \"In vitro phase separation assays, tyrosine phosphorylation assays, C. elegans neurodegeneration model with Fyn expression, NMR\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro phosphorylation with phase separation assays, in vivo C. elegans rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33349959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila model expressing disease-homologous hnRNPA2B1 mutations (Hrb98DE) in fly muscle causes progressive cytoplasmic inclusion pathology containing stress granule marker ROX8 and additional RNA-binding proteins including TDP-43. Overexpression of DNAJB6/MRJ rescues inclusion formation and prevents RBP aggregation after heat shock through a physical interaction; wild-type but not disease-mutant MRJ interacted with RBPs after heat shock.\",\n      \"method\": \"Drosophila genetic model with disease-homologous mutations, immunofluorescence for inclusions, genetic epistasis (MRJ overexpression/KO), co-immunoprecipitation after heat shock\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in Drosophila model with physical interaction data, disease mutation comparison, multiple orthogonal validations\",\n      \"pmids\": [\"26744327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Heterozygous frameshift variants in HNRNPA2B1 that extend the reading frame with a novel neomorphic C-terminal sequence (escaping NMD and translated) have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and animal models, causing early-onset oculopharyngeal muscular dystrophy.\",\n      \"method\": \"Frameshift variant characterization, nuclear import receptor binding assay (karyopherin β2), cellular localization by immunofluorescence, animal models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay with karyopherin β2, localization experiments with functional consequence, 10 independent families and animal model validation\",\n      \"pmids\": [\"35484142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SUMOylated HNRNPA2B1 (HNRNPA2B1SUMO) acts as an endogenous inhibitor of RPA during normal DNA replication. HNRNPA2B1SUMO associates with RPA through recognizing the SUMO-interacting motif (SIM) of RPA, inhibiting RPA accumulation at replication forks and impeding local ATR activation. DNA damage reduces HNRNPA2B1SUMO, releasing nuclear soluble RPA to chromatin and enabling ATR activation. HNRNPA2B1 hinders homologous recombination repair by limiting RPA availability.\",\n      \"method\": \"Co-IP identifying SIM-mediated interaction, chromatin fractionation, ATR activation assays, HR repair assays, PARP inhibitor sensitivity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined molecular mechanism (SUMO-SIM interaction), multiple functional readouts (ATR activation, HR, PARP inhibitor sensitivity), single rigorous study\",\n      \"pmids\": [\"36702126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Solution NMR showed that the two RRMs of hnRNPA2 move independently in solution without RNA. hnRNPA2 RRMs bind the minimal A2RE11 RNA weakly, with NMR shifts in both RRMs upon binding. Short A2RE RNAs or longer RNAs containing this sequence completely prevent in vitro phase separation of full-length hnRNPA2 and aggregation of disease-associated mutants.\",\n      \"method\": \"Solution NMR spectroscopy, biophysical RNA binding assays, in vitro phase separation assays with RNA addition\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization of RRM-RNA interaction combined with phase separation functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32870271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In pancreatic cancer cells, inhibition of Fyn kinase activity downregulated hnRNPA2B1 expression. hnRNPA2B1 binds Bcl-x mRNA and affects its splicing, promoting formation of anti-apoptotic Bcl-xL (downregulation of hnRNPA2B1 increased pro-apoptotic Bcl-xS formation and apoptosis). Overexpression of hnRNPA2B1 rescued cells from apoptosis.\",\n      \"method\": \"Kinase-dead Fyn expression, RNA interference knockdown, Bcl-x splicing assay by RT-PCR, apoptosis assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined splicing target (Bcl-x mRNA), functional rescue by overexpression, single lab\",\n      \"pmids\": [\"21642356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Under mitochondrial respiratory stress, Akt1 phosphorylates hnRNPA2, and this phosphorylation is a crucial step for recruitment of hnRNPA2 as a transcriptional coactivator to stress target promoters (including NFκB/cRel:p50, C/EBPδ, CREB, NFAT pathways), culminating in transcription activation of nuclear genes including Cathepsin L, RyR1, Glut4 and Akt1.\",\n      \"method\": \"In vivo phosphorylation assays, chromatin immunoprecipitation at stress target promoters, transcription activation assays with dominant-negative constructs\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation established with ChIP showing promoter recruitment, functional outcome measured, single lab\",\n      \"pmids\": [\"20153290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPA2/B1 binds the COX-2 core promoter to activate COX-2 expression in non-small-cell lung cancer. hnRNPA2/B1 interacts directly with the transcriptional co-activator p300, which acetylates hnRNPA2/B1. Acetylation by p300 (requiring its HAT domain) enhances hnRNPA2/B1 binding to the COX-2 promoter and promotes COX-2 expression and tumor growth.\",\n      \"method\": \"ChIP (promoter binding), Co-IP (hnRNPA2B1-p300 interaction), acetylation assays with p300 HAT domain deletion mutant, shRNA/siRNA knockdown with functional readouts\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with mutagenesis of HAT domain, single lab\",\n      \"pmids\": [\"26774881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"hnRNPA2 functions as a lysine acetyltransferase (KAT) that acetylates histone H4 at lysine 8 (H4K8) at telomeres under mitochondrial dysfunction. This H4K8 acetylation is associated with telomere attrition. Expression of a KAT-mutant hnRNPA2 rescued telomere length, suggesting impaired H4K8 acetylation is responsible.\",\n      \"method\": \"KAT activity assay, histone acetylation assay (H4K8), telomere length measurement, KAT-mutant hnRNPA2 expression rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity established with mutagenesis rescue, single lab, single study\",\n      \"pmids\": [\"30427907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPA2B1 binds the 3'-UTR of HIF-1α mRNA through its C-terminal glycine-rich domain, promoting HIF-1α translation. The small molecule MO-460 inhibits initiation of HIF-1α translation by binding to the C-terminal glycine-rich domain of hnRNPA2B1 and blocking its binding to HIF-1α mRNA 3'-UTR.\",\n      \"method\": \"RNA immunoprecipitation showing hnRNPA2B1-HIF-1α mRNA 3'UTR interaction, chemical proteomics identifying MO-460 binding site, translation assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP binding assay with domain mapping, small molecule disruption of function, single lab\",\n      \"pmids\": [\"30755586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"M1 muscarinic receptor signaling controls hnRNPA2/B1 protein levels by regulating mRNA translation via nonsense-mediated decay regulation, not by altering mRNA levels, protein aggregation, or degradation. Genetic mouse models with decreased or increased cholinergic tone show corresponding changes in hnRNPA2/B1 protein levels.\",\n      \"method\": \"Genetic mouse models (cholinergic tone manipulation), M1 muscarinic receptor knockout, translation assays, NMD pathway analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models with defined receptor pathway, translational mechanism established, single lab\",\n      \"pmids\": [\"27277805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPA2/B1 localization shifts from nucleus to cytoplasm during mammalian embryonic development, regulated by METTL3-dependent m6A RNA methylation. METTL3 KD blastocysts show increased mislocalization of hnRNPA2/B1, and hnRNPA2/B1 KD causes developmental arrest after the 4-cell stage with decreased OCT4 and SOX2 inner cell mass markers.\",\n      \"method\": \"Immunofluorescence localization in embryos, hnRNPA2/B1 and METTL3 knockdown with developmental readout, RNA-seq in KD blastocysts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional developmental consequences, METTL3-hnRNPA2B1 epistasis established, single lab\",\n      \"pmids\": [\"31201338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In uninfected HEp-2 cells, hnRNPA2B1 is localized in the nucleus and is not a component of exosomes. Upon HSV-1 infection, hnRNPA2B1 is quantitatively exported to the cytoplasm where a fraction colocalizes with a Golgi marker. In ΔhnRNPA2B1 cells, there is a >10-fold reduction in HSV-1 released through the apical surface, but no significant impact on basolateral cell-to-cell transfer.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence colocalization with Golgi marker, hnRNPA2B1 knockout cells, viral yield quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (viral egress), knockout with specific directional readout, single lab\",\n      \"pmids\": [\"32295924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Epirubicin disrupts the interaction between hnRNPA2B1 and miR-503 in endothelial cells, leading to hnRNPA2B1 relocalization to the nucleus while miR-503 and ANXA2 are sorted into exosomes. hnRNPA2B1 negatively regulates exosomal sorting of miR-503, establishing that RNA-binding proteins can inhibit exosomal miRNA export.\",\n      \"method\": \"Biotinylated miR-503 pulldown with mass spectrometry identification, western blotting validation, knockdown systems with pulldown analysis, localization assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown validated by MS and western blot, knockdown with specific sorting readout, single lab\",\n      \"pmids\": [\"31894362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPA2B1 is associated with stress granules (SGs) and represses their disassembly. hnRNPA2B1 absence specifically enhances arsenite-induced SG disassembly via the ubiquitin-proteasome system (not autophagy). hnRNPA2B1 interacts with core SG proteins G3BP1, G3BP2, USP10, and Caprin-1; its depletion reduces the G3BP1-USP10/Caprin-1 interaction and elevates G3BP1 ubiquitination. Hnrnpa2b1 KO in mice causes Sertoli cell-only syndrome and complete male infertility.\",\n      \"method\": \"Co-IP identifying SG protein interactions, ubiquitination assays, proteasome inhibitor experiments, autophagy inhibitor experiments, Hnrnpa2b1 KO mouse model with fertility phenotype\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods identifying specific interactions and mechanism (USP10/G3BP1/ubiquitination axis), in vivo KO model with defined phenotype\",\n      \"pmids\": [\"38363675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In PAH pulmonary arterial smooth muscle cells, hnRNPA2B1 expression and nuclear localization are increased. hnRNPA2B1 promotes expression of mRNAs carrying three defined binding motifs involved in different aspects of the cell cycle. RNA immunoprecipitation confirmed binding to target mRNAs. hnRNPA2B1 silencing decreased target mRNA levels and reduced proliferation and resistance to apoptosis in PAH-PASMC. In vivo hnRNPA2B1 inhibition in lungs rescued pulmonary hypertension in rats.\",\n      \"method\": \"RNA immunoprecipitation, bioinformatics motif analysis, hnRNPA2B1 silencing with proliferation/apoptosis readouts, immunofluorescence localization, monocrotaline rat model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP validation of targets, localization experiment with functional consequence, in vivo rescue, single lab\",\n      \"pmids\": [\"35993245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPA2B1 mediates nuclear export of m6A-tagged mRNAs through the ALYREF/NXF1 complex. ISGylation of hnRNPA2B1 (mediated by PCAT6 serving as scaffold between ISG15 and hnRNPA2B1) protects hnRNPA2B1 from ubiquitination-mediated proteasomal degradation, enhancing its ability to selectively export m6A-modified mRNAs.\",\n      \"method\": \"Co-IP (PCAT6-ISG15-hnRNPA2B1 complex, hnRNPA2B1-ALYREF/NXF1), ISGylation assay, ubiquitination assay, nuclear mRNA export assay, hnRNPA2B1 knockdown\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP interactions establishing a complex, PTM (ISGylation) protecting from ubiquitination, mRNA export functional assay, single lab\",\n      \"pmids\": [\"38626369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPA2B1 mediates microRNA processing (specifically miR-92a-2-5p and miR-373-3p) via interaction with DGCR8 (confirmed by Co-IP). These processed miRNAs are transported in exosomes to recipient monocytes or mesenchymal stem cells to activate osteoclastogenesis and suppress osteoblastogenesis by inhibiting IRF8 or RUNX2.\",\n      \"method\": \"RNA pull-down, RIP assays for hnRNPA2B1-pri-miRNA interaction, Co-IP for hnRNPA2B1-DGCR8, exosome isolation and characterization, luciferase assay for miRNA targets\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down and RIP validated, Co-IP for DGCR8, functional downstream assays, single lab\",\n      \"pmids\": [\"36451863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HNRNPA2B1 interacts with KRAS mRNA and facilitates its nuclear export and translation in colorectal cancer. The lncRNA CRNDE maintains HNRNPA2B1 protein stability by inhibiting E3 ubiquitin ligase TRIM21-mediated K63 ubiquitination-dependent degradation. The CRNDE/hnRNPA2B1 axis activates MAPK signaling through KRAS.\",\n      \"method\": \"RNA immunoprecipitation for KRAS mRNA binding, nuclear export assay, ubiquitination assay identifying TRIM21 as E3 ligase, Co-IP, CRISPR KO experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, ubiquitination mechanism defined, nuclear export functional assay, single lab\",\n      \"pmids\": [\"37716979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Linc01232 physically interacts with the RNA recognition motif 2 domain of HNRNPA2B1 (680-890 nt fragment) and inhibits its ubiquitin-mediated degradation, stabilizing HNRNPA2B1. Stabilized HNRNPA2B1 participates in alternative splicing of A-Raf, regulating the MAPK/ERK signaling pathway.\",\n      \"method\": \"RNA pull-down, RIP assays, domain mapping of HNRNPA2B1 interaction region, ubiquitination assays, RNA-seq for alternative splicing\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down with domain mapping, ubiquitination assay, splicing outcome measured, single lab\",\n      \"pmids\": [\"32814086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPA2/B1 regulates copper homeostasis by modulating the abundance of Cu(I)-transporter ATP7A via the 3' UTR of the ATP7A transcript in an isoform-dependent manner. Downregulation of B1 and B1b isoforms is sufficient to elevate ATP7A, while overexpression of either hnRNPA2 or hnRNPB1 isoforms decreases ATP7A mRNA levels.\",\n      \"method\": \"siRNA knockdown of specific isoforms, isoform-specific overexpression, 3'UTR reporter assay, mRNA and protein quantification, copper level measurement\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific functional dissection with 3'UTR mechanistic link, multiple isoform conditions tested, single lab\",\n      \"pmids\": [\"36545508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPA2B1 is a sensor for the metabolite adenine in the nucleus. Adenine directly binds and activates hnRNPA2B1, which is then recruited to Il1b enhancers. hnRNPA2B1 increases Il1b enhancer chromatin accessibility by binding and recruiting nucleolin and the demethylase FTO to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation, thereby increasing IL-1β production during bacterial infection.\",\n      \"method\": \"Large-scale metabolite-hnRNPA2B1 interaction screen, direct binding assay (adenine-hnRNPA2B1), ChIP at Il1b enhancers, chromatin accessibility assay, Co-IP with nucleolin and FTO, myeloid-specific cKO mice with bacterial infection\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding screen, ChIP, chromatin accessibility, Co-IP with specific recruiters, in vivo cKO model with rescue by IL-1β, multiple orthogonal methods\",\n      \"pmids\": [\"39814017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A hnRNPA2B1 agonist compound PAC5 binds near Asp49 in the RNA recognition motif of hnRNPA2B1, activating it and promoting its translocation to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to type I IFN production with antiviral activity against HBV and SARS-CoV-2.\",\n      \"method\": \"Binding site characterization by structural analysis (near Asp49 in RRM), nuclear-cytoplasmic fractionation, TBK1-IRF3 activation assay, in vivo HBV and hamster SARS-CoV-2 models\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site defined, translocation with functional consequence, in vivo efficacy, single lab\",\n      \"pmids\": [\"36726760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPA2B1 stabilizes SREBP2 mRNA via m6A modification and similarly stabilizes LDLR mRNA in an m6A-dependent manner, triggering de novo cholesterol synthesis through HMGCR induction and promoting glioma stemness.\",\n      \"method\": \"RNA immunoprecipitation for SREBP2/LDLR mRNA binding, m6A MeRIP sequencing, RNA stability assay, hnRNPA2B1 ablation with transcriptome and lipidomic readouts\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and MeRIP defining m6A-dependent binding, RNA stability assay, single lab\",\n      \"pmids\": [\"38070488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HNRNPA2B1 mediates exclusion of cassette exon 11 from MST1R pre-mRNA (validated by minigene model), generating the RON∆165 isoform that activates Akt/PKB signaling in head and neck cancer. Depletion of HNRNPA2B1 by CRISPR/Cas9 causes exon 11 inclusion, reducing RON∆165 and inhibiting Akt/PKB signaling, leading to reduced EMT.\",\n      \"method\": \"CRISPR/Cas9 knockout, MST1R-minigene splicing assay, isoform-specific RT-PCR, Akt/PKB signaling assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene validation of specific exon skipping, CRISPR KO with pathway readout, single lab\",\n      \"pmids\": [\"32669614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nm23-H1 increases the protein stability of hnRNPA2/B1 and both are co-recruited to the 5'UTR of Sp1 mRNA to regulate its cap-independent (IRES-mediated) translational activity in lung cancer cells.\",\n      \"method\": \"Co-IP of Nm23-H1 and hnRNPA2/B1, RNA immunoprecipitation of 5'UTR of Sp1 mRNA, IRES-based reporter assay, protein stability assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RIP of mRNA 5'UTR, IRES reporter functional assay, single lab\",\n      \"pmids\": [\"28831131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNP-A2/B1 binds directly to the ASCL1 mRNA 5'- and 3'-UTRs (identified by RNA pulldown and MALDI/TOF-MS) and functions as a key positive regulator of ASCL1 expression. Downregulation of hnRNP-A2/B1 during hypoxia is associated with post-transcriptional suppression of hASH1 synthesis.\",\n      \"method\": \"RNA pulldown with MALDI/TOF-MS identification, reporter gene assays for 5'- and 3'-UTR function, siRNA knockdown, hypoxia exposure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown with MS identification, reporter assays for UTR function, single lab\",\n      \"pmids\": [\"25124043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CSNK1D (casein kinase 1 delta) phosphorylates HNRNPA2B1 to enhance its stability. Phosphorylated/stabilized HNRNPA2B1 promotes maturation of miR-25-3p and miR-93-5p by recognizing m6A marks on primary miR-25/93 transcripts. miR-93-5p targets BAMBI to activate TGF-β pathway; miR-25-3p targets FOXO3 to inactivate FOXO pathway.\",\n      \"method\": \"Mass spectrometry identifying CSNK1D as kinase, phosphorylation and stability assays, m6A RIP for pri-miRNA binding, pri-miRNA processing assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of kinase, PTM stability mechanism, m6A-dependent pri-miRNA processing, single lab\",\n      \"pmids\": [\"37208565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARP1 and HNRNPA2B1 specifically bind DNA sequences at the termini of 'forum domains' — chromosomal regions of 50-250 kb flanked by DNA double-strand break hot spots that contain coordinately expressed genes, suggesting a structural role in coordinated transcription of gene clusters.\",\n      \"method\": \"Genome-wide mapping of blunt-ended DSBs, ChIP-seq for PARP1 and HNRNPA2B1 binding at domain termini\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-seq binding data establishing genomic localization, single lab, no functional perturbation\",\n      \"pmids\": [\"23593027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPA2B1 interacts with PABPC1, and this complex coordinates with the cap-binding eIF4F complex to facilitate translation of CIP2A, DLAT, and GPX1 mRNAs independent of m6A modification in gastric cancer cells. H. pylori infection induces hnRNPA2B1 upregulation through NF-κB recruitment to its promoter.\",\n      \"method\": \"Mass spectrometry and Co-IP for hnRNPA2B1-PABPC1 interaction, Ribo-seq and polysome profiling for translational regulation, RIP-seq for mRNA targets, m6A epitranscriptomic microarray\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP validated by MS, polysome profiling for translation, m6A microarray distinguishing m6A-independent mechanism, single lab\",\n      \"pmids\": [\"38887155\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPA2B1 is a multifunctional RNA-binding protein that acts as a nuclear m6A reader (binding m6A-modified RNAs via its RRM domains), promotes primary miRNA processing by interacting with the DGCR8 Microprocessor complex, regulates alternative splicing and polyadenylation of thousands of transcripts, controls miRNA sorting into exosomes through sumoylation-regulated EXO-motif recognition, senses viral and bacterial-derived nucleic acids/metabolites to trigger innate immune signaling via TBK1-IRF3 after JMJD6-mediated demethylation and cytoplasmic translocation, forms functional liquid-liquid phase-separated granules through its intrinsically disordered low-complexity domain whose pathogenic mutations (e.g., D290V) stabilize amyloid-like fibrils causing multisystem proteinopathy, acts as a transcriptional coactivator upon Akt1-mediated phosphorylation during mitochondrial stress, represses stress granule disassembly by stabilizing the G3BP1-USP10/Caprin-1 interaction, inhibits RPA accumulation at replication forks in its SUMOylated form to regulate ATR activation and DNA repair, and is regulated by multiple post-translational modifications including sumoylation, arginine methylation (by PRMT), tyrosine phosphorylation (by Fyn), acetylation (by p300), and ubiquitination (by TRIM21/FBXO11).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPA2B1 is a multifunctional, modification-regulated RNA-binding protein that couples RNA metabolism to gene expression, genome maintenance, innate immunity, and proteostasis [#1, #6]. In the nucleus it acts as a reader of N6-methyladenosine, binding m6A-marked transcripts through its RRM domains to direct alternative splicing, promote Microprocessor-dependent primary miRNA processing via interaction with DGCR8, and mediate nuclear export of m6A-tagged mRNAs through the ALYREF/NXF1 pathway [#1, #28]. Genome-wide it binds UAGG-containing sites in thousands of transcripts and governs alternative splicing and polyadenylation, including disease-relevant targets in motor neurons [#6]. Its intrinsically disordered low-complexity (prion-like) domain drives liquid–liquid phase separation and assembly of stress-granule-associated, amyloid-like cross-β polymers; pathogenic mutations in this domain (e.g., D290V, P298L) strengthen a steric zipper, stabilize self-seeding fibrils, and drive cytoplasmic inclusion formation, while RNA binding and arginine methylation oppose phase separation [#2, #3, #7, #16]. Heterozygous PrLD missense mutations and reading-frame-extending frameshift variants that impair karyopherin-β2 binding cause multisystem proteinopathy and early-onset oculopharyngeal muscular dystrophy, respectively [#2, #14]. HNRNPA2B1 stabilizes stress granules by maintaining the G3BP1–USP10/Caprin-1 interaction, and Hnrnpa2b1 loss in mice causes Sertoli-cell-only syndrome and male infertility [#26]. It functions as a nucleic-acid and metabolite sensor in innate immunity: it senses viral DNA, homodimerizes, and after JMJD6-mediated arginine demethylation translocates to the cytoplasm to activate TBK1-IRF3 and type I IFN production, and it senses nuclear adenine to remodel Il1b enhancer chromatin via nucleolin and FTO [#4, #33]. Its activity is tuned by an extensive set of post-translational modifications—sumoylation, arginine methylation, tyrosine phosphorylation by Fyn, acetylation by p300, ISGylation, and ubiquitination by TRIM21—that control its localization, stability, phase behavior, and substrate selection [#0, #4, #12, #15, #28, #30]. SUMOylated HNRNPA2B1 additionally restrains RPA accumulation at replication forks to limit ATR activation and homologous recombination repair [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that HNRNPA2 acts beyond RNA metabolism as a stress-responsive transcriptional coactivator, linking mitochondrial stress signaling to nuclear gene transcription.\",\n      \"evidence\": \"In vivo phosphorylation assays and ChIP at stress target promoters with dominant-negative constructs under mitochondrial respiratory stress\",\n      \"pmids\": [\"20153290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect promoter binding not structurally resolved\", \"Generality beyond the specific stress promoters tested unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the prion-like domain as the structural basis of disease, showing PrLD mutations strengthen a steric zipper to drive self-seeding fibrils and cytoplasmic inclusions.\",\n      \"evidence\": \"Fibril assembly and seeding assays, stress granule imaging in cells and animal models, mutagenesis\",\n      \"pmids\": [\"23455423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic fibril architecture not yet resolved at this stage\", \"In vivo trigger of pathological transition not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified HNRNPA2B1 as the RNA-binding protein controlling sequence-specific loading of miRNAs into exosomes, regulated by sumoylation.\",\n      \"evidence\": \"RNA immunoprecipitation, sumoylation assays, and EXO-motif mutagenesis with exosomal miRNA readout\",\n      \"pmids\": [\"24356509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO site and machinery not fully mapped\", \"Mechanism coupling sumoylation to RNA affinity unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established HNRNPA2B1 as a nuclear m6A reader that couples the mark to alternative splicing and Microprocessor-dependent pri-miRNA processing via DGCR8.\",\n      \"evidence\": \"In vitro and in vivo RIP, splicing assays, METTL3/HNRNPA2B1 knockdown epistasis, and Co-IP with DGCR8\",\n      \"pmids\": [\"26321680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct m6A contact vs. structural remodeling debated\", \"Selectivity rules for which m6A transcripts are read not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed the LC domain adopts the same cross-β polymeric conformation in hydrogels, droplets, and native nuclei, arguing for a physiological role of LC polymerization.\",\n      \"evidence\": \"Molecular footprinting of LC polymeric state, hydrogel preparation, EM, and analysis of isolated nuclei\",\n      \"pmids\": [\"26544936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional readout of nuclear polymerization not directly measured\", \"Reversibility in vivo not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped transcriptome-wide binding (UAGG motifs) and a role in alternative polyadenylation and splicing, connecting loss of function and the D290V mutant to ALS-relevant mis-splicing.\",\n      \"evidence\": \"CLIP-seq in mouse spinal cord, RNA-seq upon knockdown, and patient fibroblast/iPSC-motor neuron analysis\",\n      \"pmids\": [\"27773581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal contribution of individual splicing targets to disease unproven\", \"Mechanism linking insolubility to splicing defects unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural insight into LC-domain disorder and phase separation, and showed arginine methylation suppresses phase separation while disease mutations enhance aggregation.\",\n      \"evidence\": \"NMR spectroscopy, in vitro phase separation and arginine methylation assays, mutagenesis\",\n      \"pmids\": [\"29358076\", \"30279180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous methylation stoichiometry not measured\", \"Cross-seeding of TDP-43 in vivo not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated regulation of phase behavior by Fyn-SH3 binding to the LC domain, defining a kinase–client interface controlling granule assembly.\",\n      \"evidence\": \"Solution NMR and in vitro phase separation microscopy\",\n      \"pmids\": [\"30397184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of Fyn-SH3 recruitment not measured here\", \"Stoichiometry in physiological granules unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed HNRNPA2B1 as a nuclear viral-DNA sensor that, after JMJD6-mediated arginine demethylation, translocates to the cytoplasm to drive TBK1-IRF3 type I IFN signaling.\",\n      \"evidence\": \"Co-IP, JMJD6 demethylation assays, nuclear-cytoplasmic fractionation, TBK1-IRF3 activation, and m6A RIP on CGAS/IFI16/STING mRNAs\",\n      \"pmids\": [\"31320558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-binding mode not structurally resolved\", \"How demethylation triggers nuclear export mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved wild-type vs. D290V fibril architecture at atomic resolution, explaining how the mutation thermodynamically stabilizes pathogenic polymers.\",\n      \"evidence\": \"CryoEM of the LCD fibril core, crystal structure of the D290V segment, and energetic calculations\",\n      \"pmids\": [\"32796831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between in vitro fibril and in vivo inclusion structure not established\", \"Therapeutic targetability of the zipper untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed RRM-bound A2RE RNA suppresses phase separation and aggregation, establishing RNA as a built-in regulator of HNRNPA2B1 condensation.\",\n      \"evidence\": \"Solution NMR of RRM–RNA interaction and in vitro phase separation assays with RNA addition\",\n      \"pmids\": [\"32870271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA concentrations relevant in vivo not defined\", \"Whether endogenous RNAs protect cells from aggregation untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated Fyn tyrosine phosphorylation reduces phase separation and disease-variant aggregation and rescues neurodegeneration in vivo.\",\n      \"evidence\": \"In vitro tyrosine phosphorylation and phase separation assays plus C. elegans Fyn-expression rescue\",\n      \"pmids\": [\"33349959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian in vivo phosphorylation dynamics not measured\", \"Phosphosite occupancy under stress unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a non-canonical genome-protective role: SUMOylated HNRNPA2B1 sequesters RPA via its SIM to limit fork RPA loading and ATR activation, tuning DNA repair.\",\n      \"evidence\": \"Co-IP defining SUMO-SIM interaction, chromatin fractionation, ATR activation, HR assays, and PARP inhibitor sensitivity\",\n      \"pmids\": [\"36702126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase responsible not identified\", \"Crosstalk with HNRNPA2B1's RNA functions during replication stress unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined HNRNPA2B1 as a repressor of stress-granule disassembly through the G3BP1-USP10/Caprin-1 axis and as essential for spermatogenesis in vivo.\",\n      \"evidence\": \"Co-IP, ubiquitination and proteasome/autophagy inhibitor assays, and Hnrnpa2b1 KO mouse fertility phenotyping\",\n      \"pmids\": [\"38363675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. scaffold role in the G3BP1 complex unresolved\", \"Link between SG regulation and the infertility phenotype not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ISGylation to control of HNRNPA2B1 stability and selective m6A-mRNA nuclear export via ALYREF/NXF1.\",\n      \"evidence\": \"Co-IP of PCAT6-ISG15-HNRNPA2B1 and HNRNPA2B1-ALYREF/NXF1, ISGylation and ubiquitination assays, and mRNA export assays\",\n      \"pmids\": [\"38626369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ISGylation site not mapped\", \"Competition between ISGylation and ubiquitination not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended HNRNPA2B1's sensor function to a small metabolite, showing nuclear adenine binding activates it to remodel Il1b enhancer chromatin and drive IL-1β during bacterial infection.\",\n      \"evidence\": \"Metabolite-protein interaction screen, direct adenine binding, ChIP and chromatin accessibility at Il1b enhancers, Co-IP with nucleolin/FTO, and myeloid cKO mice\",\n      \"pmids\": [\"39814017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adenine-binding pocket structure not resolved\", \"Generality to other metabolites and enhancers untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPA2B1's many post-translational modifications are integrated to switch it between its nuclear RNA-processing, condensate, genome-protective, and cytoplasmic immune-sensing states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating SUMO/methyl/phospho/acetyl/ISG/ubiquitin marks\", \"Quantitative partitioning between competing functions in a single cell unknown\", \"Structural basis for RRM-mediated nucleic-acid and metabolite sensing incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 6, 16, 21, 27, 35, 38]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 29, 39]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 33, 40]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [18, 19, 33]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 33]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 15, 24, 40]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 23, 24, 34]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 25, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 6, 28, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 33, 34]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [18, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [18, 19, 33]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [28, 30]}\n    ],\n    \"complexes\": [\n      \"Microprocessor (with DGCR8)\",\n      \"stress granule (G3BP1/USP10/Caprin-1)\",\n      \"ALYREF/NXF1 mRNA export complex\"\n    ],\n    \"partners\": [\n      \"DGCR8\",\n      \"JMJD6\",\n      \"G3BP1\",\n      \"USP10\",\n      \"Caprin-1\",\n      \"PABPC1\",\n      \"TRIM21\",\n      \"Fyn\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}