{"gene":"IVNS1ABP","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1998,"finding":"NS1-BP (IVNS1ABP) was identified as a novel human 70-kDa protein that directly interacts with the influenza A virus NS1 protein, confirmed by yeast interaction trap and GST-pulldown (GST-NS1-BP fusion protein coprecipitated NS1 protein from solution). NS1-BP contains an N-terminal BTB/POZ domain and five kelch-like repeats. In non-infected cells, NS1-BP localizes to nuclear regions enriched with the spliceosome assembly factor SC35. In influenza A-infected cells, NS1-BP relocalizes throughout the nucleoplasm away from SC35 domains. A truncated NS1-BP mutant added to HeLa cell nuclear extract inhibited pre-mRNA splicing but not spliceosome assembly, suggesting NS1-BP promotes pre-mRNA splicing.","method":"Yeast two-hybrid (interaction trap), GST pulldown, affinity-purified antibody immunofluorescence localization, in vitro pre-mRNA splicing assay with truncated dominant-negative NS1-BP mutant","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic interaction confirmed by GST pulldown, localization by immunofluorescence, functional splicing assay; multiple orthogonal methods in one rigorous study","pmids":["9696811"],"is_preprint":false},{"year":2013,"finding":"NS1-BP (IVNS1ABP) forms a complex with multiple hnRNPs (A1, K, L, M) and regulates alternative splicing of the influenza A virus M1 mRNA segment. Knockdown of NS1-BP specifically impaired M1-to-M2 mRNA splicing without affecting NS or other M-segment splice variants. NS1-BP did not directly bind viral M1 mRNA (shown by formaldehyde and UV cross-linking), but its interacting partners hnRNP A1, K, L, and M did. hnRNP K was identified as a major mediator of M1 mRNA splicing. Reduction of NS1-BP and/or hnRNP K altered M2/M1 mRNA and protein ratios, decreasing M2 levels and inhibiting influenza virus replication.","method":"Proteomics (co-IP/MS), formaldehyde and UV cross-linking, siRNA knockdown, RT-PCR splicing assays, Western blot, virus replication assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, cross-linking, siRNA KD, functional assays) in one study, later replicated","pmids":["23825951"],"is_preprint":false},{"year":2007,"finding":"NS1-BP (IVNS1ABP) interacts with alpha-enolase and its nuclear isoform MBP-1 in vitro and in vivo. NS1-BP enhances MBP-1-mediated repression of c-Myc promoter transcription. Overexpression of both NS1-BP and MBP-1 increased repression of basal c-Myc transcription and reduced endogenous c-Myc mRNA levels. NS1-BP was also found to interact with actin in human cells.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, cotransfection/reporter assays, RT-PCR for endogenous c-Myc mRNA","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pulldown plus functional reporter assay, single lab, multiple orthogonal methods","pmids":["17996313"],"is_preprint":false},{"year":2018,"finding":"NS1-BP (IVNS1ABP) and hnRNP K directly bind the influenza A virus M mRNA downstream of the M2 5' splice site. NS1-BP binds most proximal to the 5'ss, partially overlapping the U1 snRNP binding site, while hnRNP K binds further downstream and promotes U1 snRNP recruitment. Mutation of either or both the hnRNP K and NS1-BP binding sites in M segment results in mis-splicing and attenuated IAV replication. NS1-BP and hnRNP K also regulate host pre-mRNA splicing events, and viral infection causes mis-splicing of some of these host transcripts.","method":"RNA immunoprecipitation, CLIP, mutagenesis of RNA binding sites, splicing assays, virus replication assays, RNA-seq","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct RNA binding mapped by CLIP/mutagenesis, functional rescue experiments, replicated prior finding with mechanistic extension","pmids":["29921878"],"is_preprint":false},{"year":2024,"finding":"NS1-BP (IVNS1ABP) interacts with the mRNA export receptor NXF1 and competes with the viral NS1 protein for NXF1 binding, allowing NXF1 recruitment to M1 and M2 mRNAs after splicing. NS1-BP facilitates M mRNA nuclear export via NXF1 and the TREX-2 component GANP (germinal center-associated nuclear protein). NS1-BP and NS1 remain in complex with GANP-NXF1 but dissociate at the nuclear pore complex, allowing M mRNAs to be exported to the cytoplasm.","method":"Co-immunoprecipitation, competition binding assays, RNA immunoprecipitation, nuclear export assays, cell biological imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional nuclear export assays, single lab, multiple biochemical and cell biological methods","pmids":["39384042"],"is_preprint":false},{"year":2015,"finding":"KLHL39 (an alias of IVNS1ABP per HGNC) is recruited to the substrate-binding (kelch repeat) domain of KLHL20 but is not itself a substrate of the Cul3-KLHL20 E3 ligase complex. KLHL39 does not bind Cul3 due to absence of conserved residues in its BTB domain. KLHL39 blocks KLHL20-mediated ubiquitination of PML and DAPK by disrupting their binding to KLHL20 and also disrupting KLHL20 binding to Cul3, thereby stabilizing PML and DAPK and suppressing colon cancer metastasis.","method":"Co-immunoprecipitation, ubiquitination assays, mutagenesis, in vitro binding, in vivo metastasis models, cell migration/invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (Co-IP, ubiquitination, binding), functional rescue, single lab","pmids":["25619834"],"is_preprint":false},{"year":2026,"finding":"A homozygous mutation in IVNS1ABP causes a progeroid syndrome with severe neuropathy. Patient-derived and isogenic iPSC-derived fibroblasts, iPSCs, and neural progenitor cells (NPCs) with mutant IVNS1ABP exhibited defective cytokinesis, increased DNA damage, and premature cellular senescence. Cerebral organoids showed early/premature differentiation of NPCs into neurons. Biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin and actin-associated proteins, leading to dysregulated actin dynamics during cytokinesis.","method":"Exome sequencing, iPSC generation and differentiation, cerebral organoids, cytokinesis assays, DNA damage assays, senescence assays, co-immunoprecipitation/binding assays for actin interaction, molecular profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic iPSC disease model with multiple orthogonal cellular and biochemical readouts, loss-of-function with defined phenotype, published peer-reviewed","pmids":["41857046"],"is_preprint":false},{"year":2024,"finding":"Loss of IVNS1ABP (a close gigaxonin paralogue and E3-ubiquitin ligase adaptor) leads to hallmarks of protein accumulation and lysosomal dysfunction in patient-derived fibroblasts, iPSCs, and neural progenitors. Ubiquitome analysis revealed overlapping substrates with gigaxonin, including Vimentin and MAP1B. Biallelic correction to isogenic wildtype in disease-relevant motor neurons partly rescued cellular vulnerabilities. A zebrafish ivns1abpa/b double knockout partially recapitulated peripheral neuropathy, showing aberrant primary motor neuron axon pathfinding and impaired locomotion.","method":"Patient-derived iPSC models, ubiquitome mass spectrometry, isogenic correction, zebrafish knockout, motor neuron differentiation, lysosomal function assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ubiquitome MS, zebrafish KO, iPSC rescue), preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"Mutant IVNS1ABP shows altered binding to actin and actin-associated proteins, resulting in disrupted actin filament organization and dysregulated actin dynamics during cytokinesis, leading to cellular senescence in patient-derived neural progenitor cells.","method":"Co-immunoprecipitation, actin polymerization assays, live cell imaging of cytokinesis, senescence markers, isogenic iPSC-derived NPCs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical binding assays plus functional cellular phenotypes in isogenic model, preprint","pmids":[],"is_preprint":true},{"year":2018,"finding":"In ESCC cells, NS1-BP (IVNS1ABP) overexpression repressed c-Myc expression, inhibited cell proliferation, and promoted apoptosis, while NS1-BP knockdown induced c-Myc expression, increased proliferation, and repressed apoptosis, indicating NS1-BP acts as a negative regulator of c-Myc with consequent effects on ESCC cell growth.","method":"Transient transfection (overexpression and knockdown), Western blot for c-Myc, MTT proliferation assay, flow cytometry for apoptosis","journal":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of methods per condition, no pathway mechanism beyond c-Myc level change","pmids":["29365413"],"is_preprint":false}],"current_model":"IVNS1ABP (NS1-BP) is a BTB/POZ-kelch domain protein that: (1) directly binds influenza A virus NS1 protein and promotes alternative splicing of the viral M1 mRNA into M2 mRNA by recruiting hnRNP K and other hnRNPs to the M2 5' splice site; (2) competes with viral NS1 for NXF1 binding to facilitate nuclear export of viral M mRNAs via the NXF1-TREX2 pathway; (3) functions as an E3-ubiquitin ligase adaptor (gigaxonin paralogue) whose substrates include Vimentin and MAP1B, and acts as a negative regulator of Cul3-KLHL20 ubiquitin ligase by blocking substrate and Cul3 engagement; (4) interacts with alpha-enolase/MBP-1 to enhance repression of c-Myc transcription; and (5) binds actin and actin-associated proteins to regulate actin dynamics during cytokinesis, with loss-of-function mutations causing defective cytokinesis, DNA damage, cellular senescence, and a progeroid neuropathy syndrome."},"narrative":{"mechanistic_narrative":"IVNS1ABP (NS1-BP) is a BTB/POZ-kelch domain protein that operates at the intersection of viral RNA processing, ubiquitin-ligase regulation, and actin-dependent cell division [PMID:9696811, PMID:29921878, PMID:25619834, PMID:41857046]. It was first identified through its direct interaction with the influenza A virus NS1 protein and its residence in spliceosome-associated nuclear domains, where it promotes pre-mRNA splicing [PMID:9696811]. During influenza infection it nucleates a complex with multiple hnRNPs (A1, K, L, M) that drives alternative splicing of the viral M1 mRNA into M2; IVNS1ABP does not bind the M segment directly but its partner hnRNP K does, with IVNS1ABP binding the M2 5' splice site region most proximal to the U1 snRNP site while hnRNP K binds downstream to promote U1 recruitment [PMID:23825951, PMID:29921878]. The same machinery also redirects splicing of host transcripts [PMID:29921878]. After splicing, IVNS1ABP competes with NS1 for the export receptor NXF1, enabling NXF1/GANP(TREX-2)-dependent nuclear export of viral M mRNAs [PMID:39384042]. Beyond viral biology, IVNS1ABP regulates the Cul3-KLHL20 E3 ubiquitin ligase: lacking the BTB residues needed to engage Cul3, it instead binds the KLHL20 kelch domain and blocks ubiquitination of PML and DAPK, thereby stabilizing them and suppressing colon cancer metastasis [PMID:25619834]. It also interacts with alpha-enolase/MBP-1 to enhance repression of c-Myc transcription [PMID:17996313]. A homozygous IVNS1ABP mutation causes a progeroid syndrome with severe neuropathy; patient and isogenic cell models show altered binding to actin and actin-associated proteins, dysregulated actin dynamics during cytokinesis, increased DNA damage, premature senescence, and aberrant neural progenitor differentiation [PMID:41857046].","teleology":[{"year":1998,"claim":"Established IVNS1ABP as a defined human protein partner of influenza NS1 and placed it functionally in nuclear splicing compartments, answering what cellular factor NS1 engages and where.","evidence":"Yeast two-hybrid and GST pulldown for the NS1 interaction, immunofluorescence localization to SC35 domains, and an in vitro splicing assay with a dominant-negative mutant","pmids":["9696811"],"confidence":"High","gaps":["Did not identify which splicing events or RNA targets IVNS1ABP acts on","Mechanism of how a BTB-kelch protein influences splicing left undefined"]},{"year":2007,"claim":"Connected IVNS1ABP to transcriptional control by showing it partners with alpha-enolase/MBP-1 to repress c-Myc, and noted an actin interaction, broadening its functional repertoire beyond viral RNA.","evidence":"Yeast two-hybrid, reciprocal Co-IP, GST pulldown, colocalization, and c-Myc reporter/RT-PCR assays","pmids":["17996313"],"confidence":"Medium","gaps":["Single lab","Did not define how IVNS1ABP enhances MBP-1 repression mechanistically","Functional role of the actin interaction not explored"]},{"year":2013,"claim":"Defined the mechanism of IVNS1ABP in viral splicing — it assembles an hnRNP complex (notably hnRNP K) that splices M1 to M2 indirectly, since IVNS1ABP itself does not bind the RNA.","evidence":"Co-IP/MS proteomics, formaldehyde/UV cross-linking, siRNA knockdown, RT-PCR splicing assays, and virus replication assays","pmids":["23825951"],"confidence":"High","gaps":["Precise RNA elements and binding geometry not yet mapped","Extent of host splicing effects unaddressed"]},{"year":2015,"claim":"Showed IVNS1ABP (KLHL39) is a pseudo-substrate-adaptor that negatively regulates a Cullin-RING ligase, establishing a ubiquitin-pathway role distinct from its splicing function.","evidence":"Co-IP, ubiquitination assays, BTB-domain mutagenesis, in vitro binding, and in vivo colon cancer metastasis models","pmids":["25619834"],"confidence":"Medium","gaps":["Single lab","Whether IVNS1ABP itself acts as a functional E3 adaptor elsewhere not resolved here"]},{"year":2018,"claim":"Resolved the molecular geometry of viral splicing regulation by mapping where IVNS1ABP and hnRNP K bind the M2 5' splice site and how they direct U1 snRNP, and extended the activity to host transcripts.","evidence":"RNA immunoprecipitation, CLIP, RNA-binding-site mutagenesis with functional rescue, splicing assays, and RNA-seq","pmids":["29921878"],"confidence":"High","gaps":["Functional consequence of host mis-splicing for infection not fully defined","How the BTB-kelch architecture supports RNA-site occupancy unclear"]},{"year":2024,"claim":"Connected splicing to mRNA export, showing IVNS1ABP competes with NS1 for NXF1 to hand off spliced M mRNAs to the NXF1/GANP/TREX-2 export pathway.","evidence":"Co-IP, competition binding assays, RNA immunoprecipitation, and nuclear export assays with imaging","pmids":["39384042"],"confidence":"Medium","gaps":["Single lab","Stoichiometry and timing of the NS1/IVNS1ABP/NXF1 hand-off at the pore not fully resolved"]},{"year":2024,"claim":"Proposed IVNS1ABP as a gigaxonin paralogue and E3-ligase adaptor whose loss drives protein accumulation and lysosomal dysfunction via shared substrates, linking it to peripheral neuropathy.","evidence":"Patient iPSC models, ubiquitome mass spectrometry, isogenic correction, and a zebrafish ivns1abpa/b double knockout (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct ubiquitin-ligase adaptor activity of IVNS1ABP on Vimentin/MAP1B not biochemically reconstituted","Relationship between ubiquitin defect and actin/cytokinesis defect unclear"]},{"year":2026,"claim":"Demonstrated that a homozygous IVNS1ABP mutation causes a progeroid neuropathy through disrupted actin-dependent cytokinesis, defining a Mendelian disease mechanism.","evidence":"Exome sequencing, isogenic iPSC-derived fibroblasts/iPSCs/NPCs and cerebral organoids, cytokinesis/DNA-damage/senescence assays, and actin-binding Co-IP","pmids":["41857046"],"confidence":"High","gaps":["How altered actin binding mechanistically links to DNA damage and senescence not fully traced","Relationship between this actin/cytokinesis role and the protein's splicing/ubiquitin functions undefined"]},{"year":null,"claim":"It remains unresolved how IVNS1ABP's distinct activities — hnRNP-dependent splicing, NXF1 export, Cul3-KLHL20 regulation, c-Myc repression, and actin-dependent cytokinesis — are integrated into a unified function of a single BTB-kelch protein.","evidence":"No single study in the corpus reconciles the splicing, ubiquitin-adaptor, and cytoskeletal roles","pmids":[],"confidence":"Low","gaps":["No structural model linking the BTB-kelch domains to these varied activities","Whether domain partitioning or context determines which activity dominates is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5]}],"complexes":[],"partners":["NS1","HNRNP K","HNRNP A1","NXF1","KLHL20","ENO1","ACTIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6Y0","full_name":"Influenza virus NS1A-binding protein","aliases":["Aryl hydrocarbon receptor-associated protein 3","Kelch-like protein 39"],"length_aa":642,"mass_kda":71.7,"function":"Involved in many cell functions, including pre-mRNA splicing, the aryl hydrocarbon receptor (AHR) pathway, F-actin organization and protein ubiquitination. Plays a role in the dynamic organization of the actin skeleton as a stabilizer of actin filaments by association with F-actin through Kelch repeats (By similarity). Protects cells from cell death induced by actin destabilization (By similarity). Functions as modifier of the AHR/Aryl hydrocarbon receptor pathway increasing the concentration of AHR available to activate transcription (PubMed:16582008). In addition, functions as a negative regulator of BCR(KLHL20) E3 ubiquitin ligase complex to prevent ubiquitin-mediated proteolysis of PML and DAPK1, two tumor suppressors (PubMed:25619834). Inhibits pre-mRNA splicing (in vitro) (PubMed:9696811). May play a role in mRNA nuclear export (PubMed:30538201) (Microbial infection) Involved in the alternative splicing of influenza A virus M1 mRNA through interaction with HNRNPK, thereby facilitating the generation of viral M2 protein (PubMed:23825951, PubMed:9696811). The BTB and Kelch domains are required for splicing activity (PubMed:30538201). Promotes export of viral M mRNA and RNP via its interaction with mRNA export factor ALYREF (PubMed:30538201)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y6Y0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IVNS1ABP","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IVNS1ABP","total_profiled":1310},"omim":[{"mim_id":"618969","title":"IMMUNODEFICIENCY 70; IMD70","url":"https://www.omim.org/entry/618969"},{"mim_id":"609209","title":"INFLUENZA VIRUS NS1A-BINDING PROTEIN; IVNS1ABP","url":"https://www.omim.org/entry/609209"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":427.4}],"url":"https://www.proteinatlas.org/search/IVNS1ABP"},"hgnc":{"alias_symbol":["NS1-BP","HSPC068","NS-1","KIAA0850","ND1","KLHL39","ARA3"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6Y0","domains":[{"cath_id":"3.30.710.10","chopping":"15-129","consensus_level":"high","plddt":92.4,"start":15,"end":129},{"cath_id":"-","chopping":"174-236_286-322","consensus_level":"medium","plddt":84.8967,"start":174,"end":322},{"cath_id":"2.120.10.80","chopping":"351-639","consensus_level":"medium","plddt":94.0827,"start":351,"end":639}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Y0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Y0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Y0-F1-predicted_aligned_error_v6.png","plddt_mean":84.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IVNS1ABP","jax_strain_url":"https://www.jax.org/strain/search?query=IVNS1ABP"},"sequence":{"accession":"Q9Y6Y0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6Y0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6Y0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Y0"}},"corpus_meta":[{"pmid":"10482630","id":"PMC_10482630","title":"Possible interactions between the NS-1 protein and tumor necrosis factor alpha pathways in erythroid cell apoptosis induced by human parvovirus B19.","date":"1999","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10482630","citation_count":130,"is_preprint":false},{"pmid":"3339715","id":"PMC_3339715","title":"The NS-1 polypeptide of minute virus of mice is covalently attached to the 5' termini of duplex replicative-form DNA and progeny single strands.","date":"1988","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/3339715","citation_count":128,"is_preprint":false},{"pmid":"2527311","id":"PMC_2527311","title":"A genome-linked copy of the NS-1 polypeptide is located on the outside of infectious parvovirus particles.","date":"1989","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/2527311","citation_count":123,"is_preprint":false},{"pmid":"9696811","id":"PMC_9696811","title":"NS1-Binding protein (NS1-BP): a novel human protein that interacts with the influenza A virus nonstructural NS1 protein is relocalized in the nuclei of infected cells.","date":"1998","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9696811","citation_count":107,"is_preprint":false},{"pmid":"3171551","id":"PMC_3171551","title":"Minute virus of mice non-structural protein NS-1 is necessary and sufficient for trans-activation of the viral P39 promoter.","date":"1988","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/3171551","citation_count":102,"is_preprint":false},{"pmid":"2137660","id":"PMC_2137660","title":"NS-1 and NS-2 proteins may act synergistically in the cytopathogenicity of parvovirus MVMp.","date":"1990","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/2137660","citation_count":96,"is_preprint":false},{"pmid":"23825951","id":"PMC_23825951","title":"Cellular RNA binding proteins NS1-BP and hnRNP K regulate influenza A virus RNA splicing.","date":"2013","source":"PLoS 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39384042","citation_count":9,"is_preprint":false},{"pmid":"34899621","id":"PMC_34899621","title":"Iocasia fonsfrigidae NS-1 gen. nov., sp. nov., a Novel Deep-Sea Bacterium Possessing Diverse Carbohydrate Metabolic Pathways.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34899621","citation_count":9,"is_preprint":false},{"pmid":"8249286","id":"PMC_8249286","title":"Inhibition of heterologous DNA replication by the MVMp nonstructural NS-1 protein: identification of a target sequence.","date":"1993","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/8249286","citation_count":8,"is_preprint":false},{"pmid":"22783396","id":"PMC_22783396","title":"Cloning and sequencing of the light chain variable region from NS-1 myeloma.","date":"2012","source":"Oncology 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22484334","citation_count":6,"is_preprint":false},{"pmid":"8470955","id":"PMC_8470955","title":"Sequence of the NS 1 gene of the K 23 isolate of tick-borne encephalitis virus and identification of conserved motifs.","date":"1993","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8470955","citation_count":6,"is_preprint":false},{"pmid":"37126112","id":"PMC_37126112","title":"Biodegradation of Phenol Using the Indigenous Rhodococcus pyridinivorans Strain PDB9T NS-1 Immobilized in Calcium Alginate Beads.","date":"2023","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37126112","citation_count":4,"is_preprint":false},{"pmid":"22358764","id":"PMC_22358764","title":"Deletion of the κ genes from mouse hybridomas established with NS-1 myelomas.","date":"1997","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22358764","citation_count":4,"is_preprint":false},{"pmid":"30217599","id":"PMC_30217599","title":"An efficient production of hybrid recombinant protein comprising non-structural proteins (NS 1 & NS 3) of bluetongue virus in prokaryotic expression system.","date":"2018","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/30217599","citation_count":3,"is_preprint":false},{"pmid":"40782973","id":"PMC_40782973","title":"Unveiling the diagnostic and causal role of hyperlipidemia- and lipophagy-associated genes PLAUR, IVNS1ABP, and QKI in acute myocardial infarction.","date":"2025","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/40782973","citation_count":2,"is_preprint":false},{"pmid":"18394650","id":"PMC_18394650","title":"The significance of arginase I administration on the survival of mice bearing NS-1 myeloma cells.","date":"2008","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/18394650","citation_count":2,"is_preprint":false},{"pmid":"9444400","id":"PMC_9444400","title":"A preliminary analysis of antineoplastic activity of parvovirus MVMp NS-1 proteins.","date":"1997","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9444400","citation_count":2,"is_preprint":false},{"pmid":"19101593","id":"PMC_19101593","title":"Expression, purification, and characterization of recombinant NS-1, the porcine parvovirus non-structural protein.","date":"2009","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/19101593","citation_count":1,"is_preprint":false},{"pmid":"8140289","id":"PMC_8140289","title":"Expression of the non-structural proteins of parvovirus MVMp from recombinant retroviruses: predominant role of the parvoviral NS-1 product in host cell disturbance.","date":"1993","source":"Research in virology","url":"https://pubmed.ncbi.nlm.nih.gov/8140289","citation_count":1,"is_preprint":false},{"pmid":"8347083","id":"PMC_8347083","title":"Comparative analysis of the NS 1 gene sequences of dengue-1 viruses prototype Hawaii strain and Thai isolate TH-Sman, and determination of the intratypic variation of NS 1 protein among dengue-1 viruses.","date":"1993","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8347083","citation_count":1,"is_preprint":false},{"pmid":"41857046","id":"PMC_41857046","title":"IVNS1ABP mutation drives cellular senescence in newly identified progeroid neuropathy.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41857046","citation_count":0,"is_preprint":false},{"pmid":"29365413","id":"PMC_29365413","title":"[Clinical significance of NS1-BP expression in esophageal squamous cell carcinoma].","date":"2018","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/29365413","citation_count":0,"is_preprint":false},{"pmid":"14625180","id":"PMC_14625180","title":"[Establishment and identification of recombinant NS-1 cell strain that stably expresses chimeric HBc containing HBV multiepitope short peptides].","date":"2003","source":"Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA","url":"https://pubmed.ncbi.nlm.nih.gov/14625180","citation_count":0,"is_preprint":false},{"pmid":"12578576","id":"PMC_12578576","title":"[Antitumor Activities of KRN7000 in NS-1 Myeloma-Bearing Mice].","date":"2001","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/12578576","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.05.24318546","title":"The diagnostic value of hyperlipidemia and lipophagy-related genes, PLAUR, IVNS1ABP, and QKI, in acute myocardial infarction","date":"2024-12-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.05.24318546","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.12.24315363","title":"IVNS1ABP Deficiency Disrupts Actin Filament Organization and Leads to Cellular Senescence in a Newly Identified Progeroid Neuropathy Syndrome","date":"2024-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.12.24315363","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.23.24315364","title":"Loss of IVNS1ABP, a gigaxonin paralogue, leads to a progeroid neuropathy due to impaired proteostasis","date":"2024-10-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.23.24315364","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30309,"output_tokens":3320,"usd":0.070363,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10836,"output_tokens":3458,"usd":0.070315,"stage2_stop_reason":"end_turn"},"total_usd":0.140678,"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\": 1998,\n      \"finding\": \"NS1-BP (IVNS1ABP) was identified as a novel human 70-kDa protein that directly interacts with the influenza A virus NS1 protein, confirmed by yeast interaction trap and GST-pulldown (GST-NS1-BP fusion protein coprecipitated NS1 protein from solution). NS1-BP contains an N-terminal BTB/POZ domain and five kelch-like repeats. In non-infected cells, NS1-BP localizes to nuclear regions enriched with the spliceosome assembly factor SC35. In influenza A-infected cells, NS1-BP relocalizes throughout the nucleoplasm away from SC35 domains. A truncated NS1-BP mutant added to HeLa cell nuclear extract inhibited pre-mRNA splicing but not spliceosome assembly, suggesting NS1-BP promotes pre-mRNA splicing.\",\n      \"method\": \"Yeast two-hybrid (interaction trap), GST pulldown, affinity-purified antibody immunofluorescence localization, in vitro pre-mRNA splicing assay with truncated dominant-negative NS1-BP mutant\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic interaction confirmed by GST pulldown, localization by immunofluorescence, functional splicing assay; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"9696811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NS1-BP (IVNS1ABP) forms a complex with multiple hnRNPs (A1, K, L, M) and regulates alternative splicing of the influenza A virus M1 mRNA segment. Knockdown of NS1-BP specifically impaired M1-to-M2 mRNA splicing without affecting NS or other M-segment splice variants. NS1-BP did not directly bind viral M1 mRNA (shown by formaldehyde and UV cross-linking), but its interacting partners hnRNP A1, K, L, and M did. hnRNP K was identified as a major mediator of M1 mRNA splicing. Reduction of NS1-BP and/or hnRNP K altered M2/M1 mRNA and protein ratios, decreasing M2 levels and inhibiting influenza virus replication.\",\n      \"method\": \"Proteomics (co-IP/MS), formaldehyde and UV cross-linking, siRNA knockdown, RT-PCR splicing assays, Western blot, virus replication assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, cross-linking, siRNA KD, functional assays) in one study, later replicated\",\n      \"pmids\": [\"23825951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NS1-BP (IVNS1ABP) interacts with alpha-enolase and its nuclear isoform MBP-1 in vitro and in vivo. NS1-BP enhances MBP-1-mediated repression of c-Myc promoter transcription. Overexpression of both NS1-BP and MBP-1 increased repression of basal c-Myc transcription and reduced endogenous c-Myc mRNA levels. NS1-BP was also found to interact with actin in human cells.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, cotransfection/reporter assays, RT-PCR for endogenous c-Myc mRNA\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pulldown plus functional reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17996313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NS1-BP (IVNS1ABP) and hnRNP K directly bind the influenza A virus M mRNA downstream of the M2 5' splice site. NS1-BP binds most proximal to the 5'ss, partially overlapping the U1 snRNP binding site, while hnRNP K binds further downstream and promotes U1 snRNP recruitment. Mutation of either or both the hnRNP K and NS1-BP binding sites in M segment results in mis-splicing and attenuated IAV replication. NS1-BP and hnRNP K also regulate host pre-mRNA splicing events, and viral infection causes mis-splicing of some of these host transcripts.\",\n      \"method\": \"RNA immunoprecipitation, CLIP, mutagenesis of RNA binding sites, splicing assays, virus replication assays, RNA-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct RNA binding mapped by CLIP/mutagenesis, functional rescue experiments, replicated prior finding with mechanistic extension\",\n      \"pmids\": [\"29921878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NS1-BP (IVNS1ABP) interacts with the mRNA export receptor NXF1 and competes with the viral NS1 protein for NXF1 binding, allowing NXF1 recruitment to M1 and M2 mRNAs after splicing. NS1-BP facilitates M mRNA nuclear export via NXF1 and the TREX-2 component GANP (germinal center-associated nuclear protein). NS1-BP and NS1 remain in complex with GANP-NXF1 but dissociate at the nuclear pore complex, allowing M mRNAs to be exported to the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assays, RNA immunoprecipitation, nuclear export assays, cell biological imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional nuclear export assays, single lab, multiple biochemical and cell biological methods\",\n      \"pmids\": [\"39384042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KLHL39 (an alias of IVNS1ABP per HGNC) is recruited to the substrate-binding (kelch repeat) domain of KLHL20 but is not itself a substrate of the Cul3-KLHL20 E3 ligase complex. KLHL39 does not bind Cul3 due to absence of conserved residues in its BTB domain. KLHL39 blocks KLHL20-mediated ubiquitination of PML and DAPK by disrupting their binding to KLHL20 and also disrupting KLHL20 binding to Cul3, thereby stabilizing PML and DAPK and suppressing colon cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mutagenesis, in vitro binding, in vivo metastasis models, cell migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (Co-IP, ubiquitination, binding), functional rescue, single lab\",\n      \"pmids\": [\"25619834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A homozygous mutation in IVNS1ABP causes a progeroid syndrome with severe neuropathy. Patient-derived and isogenic iPSC-derived fibroblasts, iPSCs, and neural progenitor cells (NPCs) with mutant IVNS1ABP exhibited defective cytokinesis, increased DNA damage, and premature cellular senescence. Cerebral organoids showed early/premature differentiation of NPCs into neurons. Biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin and actin-associated proteins, leading to dysregulated actin dynamics during cytokinesis.\",\n      \"method\": \"Exome sequencing, iPSC generation and differentiation, cerebral organoids, cytokinesis assays, DNA damage assays, senescence assays, co-immunoprecipitation/binding assays for actin interaction, molecular profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic iPSC disease model with multiple orthogonal cellular and biochemical readouts, loss-of-function with defined phenotype, published peer-reviewed\",\n      \"pmids\": [\"41857046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of IVNS1ABP (a close gigaxonin paralogue and E3-ubiquitin ligase adaptor) leads to hallmarks of protein accumulation and lysosomal dysfunction in patient-derived fibroblasts, iPSCs, and neural progenitors. Ubiquitome analysis revealed overlapping substrates with gigaxonin, including Vimentin and MAP1B. Biallelic correction to isogenic wildtype in disease-relevant motor neurons partly rescued cellular vulnerabilities. A zebrafish ivns1abpa/b double knockout partially recapitulated peripheral neuropathy, showing aberrant primary motor neuron axon pathfinding and impaired locomotion.\",\n      \"method\": \"Patient-derived iPSC models, ubiquitome mass spectrometry, isogenic correction, zebrafish knockout, motor neuron differentiation, lysosomal function assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ubiquitome MS, zebrafish KO, iPSC rescue), preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mutant IVNS1ABP shows altered binding to actin and actin-associated proteins, resulting in disrupted actin filament organization and dysregulated actin dynamics during cytokinesis, leading to cellular senescence in patient-derived neural progenitor cells.\",\n      \"method\": \"Co-immunoprecipitation, actin polymerization assays, live cell imaging of cytokinesis, senescence markers, isogenic iPSC-derived NPCs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding assays plus functional cellular phenotypes in isogenic model, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In ESCC cells, NS1-BP (IVNS1ABP) overexpression repressed c-Myc expression, inhibited cell proliferation, and promoted apoptosis, while NS1-BP knockdown induced c-Myc expression, increased proliferation, and repressed apoptosis, indicating NS1-BP acts as a negative regulator of c-Myc with consequent effects on ESCC cell growth.\",\n      \"method\": \"Transient transfection (overexpression and knockdown), Western blot for c-Myc, MTT proliferation assay, flow cytometry for apoptosis\",\n      \"journal\": \"Zhonghua zhong liu za zhi [Chinese journal of oncology]\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of methods per condition, no pathway mechanism beyond c-Myc level change\",\n      \"pmids\": [\"29365413\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IVNS1ABP (NS1-BP) is a BTB/POZ-kelch domain protein that: (1) directly binds influenza A virus NS1 protein and promotes alternative splicing of the viral M1 mRNA into M2 mRNA by recruiting hnRNP K and other hnRNPs to the M2 5' splice site; (2) competes with viral NS1 for NXF1 binding to facilitate nuclear export of viral M mRNAs via the NXF1-TREX2 pathway; (3) functions as an E3-ubiquitin ligase adaptor (gigaxonin paralogue) whose substrates include Vimentin and MAP1B, and acts as a negative regulator of Cul3-KLHL20 ubiquitin ligase by blocking substrate and Cul3 engagement; (4) interacts with alpha-enolase/MBP-1 to enhance repression of c-Myc transcription; and (5) binds actin and actin-associated proteins to regulate actin dynamics during cytokinesis, with loss-of-function mutations causing defective cytokinesis, DNA damage, cellular senescence, and a progeroid neuropathy syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IVNS1ABP (NS1-BP) is a BTB/POZ-kelch domain protein that operates at the intersection of viral RNA processing, ubiquitin-ligase regulation, and actin-dependent cell division [#0, #3, #5, #6]. It was first identified through its direct interaction with the influenza A virus NS1 protein and its residence in spliceosome-associated nuclear domains, where it promotes pre-mRNA splicing [#0]. During influenza infection it nucleates a complex with multiple hnRNPs (A1, K, L, M) that drives alternative splicing of the viral M1 mRNA into M2; IVNS1ABP does not bind the M segment directly but its partner hnRNP K does, with IVNS1ABP binding the M2 5' splice site region most proximal to the U1 snRNP site while hnRNP K binds downstream to promote U1 recruitment [#1, #3]. The same machinery also redirects splicing of host transcripts [#3]. After splicing, IVNS1ABP competes with NS1 for the export receptor NXF1, enabling NXF1/GANP(TREX-2)-dependent nuclear export of viral M mRNAs [#4]. Beyond viral biology, IVNS1ABP regulates the Cul3-KLHL20 E3 ubiquitin ligase: lacking the BTB residues needed to engage Cul3, it instead binds the KLHL20 kelch domain and blocks ubiquitination of PML and DAPK, thereby stabilizing them and suppressing colon cancer metastasis [#5]. It also interacts with alpha-enolase/MBP-1 to enhance repression of c-Myc transcription [#2]. A homozygous IVNS1ABP mutation causes a progeroid syndrome with severe neuropathy; patient and isogenic cell models show altered binding to actin and actin-associated proteins, dysregulated actin dynamics during cytokinesis, increased DNA damage, premature senescence, and aberrant neural progenitor differentiation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established IVNS1ABP as a defined human protein partner of influenza NS1 and placed it functionally in nuclear splicing compartments, answering what cellular factor NS1 engages and where.\",\n      \"evidence\": \"Yeast two-hybrid and GST pulldown for the NS1 interaction, immunofluorescence localization to SC35 domains, and an in vitro splicing assay with a dominant-negative mutant\",\n      \"pmids\": [\"9696811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which splicing events or RNA targets IVNS1ABP acts on\", \"Mechanism of how a BTB-kelch protein influences splicing left undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected IVNS1ABP to transcriptional control by showing it partners with alpha-enolase/MBP-1 to repress c-Myc, and noted an actin interaction, broadening its functional repertoire beyond viral RNA.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, GST pulldown, colocalization, and c-Myc reporter/RT-PCR assays\",\n      \"pmids\": [\"17996313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not define how IVNS1ABP enhances MBP-1 repression mechanistically\", \"Functional role of the actin interaction not explored\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the mechanism of IVNS1ABP in viral splicing — it assembles an hnRNP complex (notably hnRNP K) that splices M1 to M2 indirectly, since IVNS1ABP itself does not bind the RNA.\",\n      \"evidence\": \"Co-IP/MS proteomics, formaldehyde/UV cross-linking, siRNA knockdown, RT-PCR splicing assays, and virus replication assays\",\n      \"pmids\": [\"23825951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise RNA elements and binding geometry not yet mapped\", \"Extent of host splicing effects unaddressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed IVNS1ABP (KLHL39) is a pseudo-substrate-adaptor that negatively regulates a Cullin-RING ligase, establishing a ubiquitin-pathway role distinct from its splicing function.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, BTB-domain mutagenesis, in vitro binding, and in vivo colon cancer metastasis models\",\n      \"pmids\": [\"25619834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether IVNS1ABP itself acts as a functional E3 adaptor elsewhere not resolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the molecular geometry of viral splicing regulation by mapping where IVNS1ABP and hnRNP K bind the M2 5' splice site and how they direct U1 snRNP, and extended the activity to host transcripts.\",\n      \"evidence\": \"RNA immunoprecipitation, CLIP, RNA-binding-site mutagenesis with functional rescue, splicing assays, and RNA-seq\",\n      \"pmids\": [\"29921878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of host mis-splicing for infection not fully defined\", \"How the BTB-kelch architecture supports RNA-site occupancy unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected splicing to mRNA export, showing IVNS1ABP competes with NS1 for NXF1 to hand off spliced M mRNAs to the NXF1/GANP/TREX-2 export pathway.\",\n      \"evidence\": \"Co-IP, competition binding assays, RNA immunoprecipitation, and nuclear export assays with imaging\",\n      \"pmids\": [\"39384042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Stoichiometry and timing of the NS1/IVNS1ABP/NXF1 hand-off at the pore not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed IVNS1ABP as a gigaxonin paralogue and E3-ligase adaptor whose loss drives protein accumulation and lysosomal dysfunction via shared substrates, linking it to peripheral neuropathy.\",\n      \"evidence\": \"Patient iPSC models, ubiquitome mass spectrometry, isogenic correction, and a zebrafish ivns1abpa/b double knockout (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct ubiquitin-ligase adaptor activity of IVNS1ABP on Vimentin/MAP1B not biochemically reconstituted\", \"Relationship between ubiquitin defect and actin/cytokinesis defect unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that a homozygous IVNS1ABP mutation causes a progeroid neuropathy through disrupted actin-dependent cytokinesis, defining a Mendelian disease mechanism.\",\n      \"evidence\": \"Exome sequencing, isogenic iPSC-derived fibroblasts/iPSCs/NPCs and cerebral organoids, cytokinesis/DNA-damage/senescence assays, and actin-binding Co-IP\",\n      \"pmids\": [\"41857046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How altered actin binding mechanistically links to DNA damage and senescence not fully traced\", \"Relationship between this actin/cytokinesis role and the protein's splicing/ubiquitin functions undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how IVNS1ABP's distinct activities — hnRNP-dependent splicing, NXF1 export, Cul3-KLHL20 regulation, c-Myc repression, and actin-dependent cytokinesis — are integrated into a unified function of a single BTB-kelch protein.\",\n      \"evidence\": \"No single study in the corpus reconciles the splicing, ubiquitin-adaptor, and cytoskeletal roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking the BTB-kelch domains to these varied activities\", \"Whether domain partitioning or context determines which activity dominates is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NS1\", \"hnRNP K\", \"hnRNP A1\", \"NXF1\", \"KLHL20\", \"ENO1\", \"actin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}