Affinage

IVNS1ABP

Influenza virus NS1A-binding protein · UniProt Q9Y6Y0

Length
642 aa
Mass
71.7 kDa
Annotated
2026-06-10
61 papers in source corpus 8 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 High

    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

    PMID:9696811

    Open questions at the time
    • Did not identify which splicing events or RNA targets IVNS1ABP acts on
    • Mechanism of how a BTB-kelch protein influences splicing left undefined
  2. 2007 Medium

    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

    PMID:17996313

    Open questions at the time
    • Single lab
    • Did not define how IVNS1ABP enhances MBP-1 repression mechanistically
    • Functional role of the actin interaction not explored
  3. 2013 High

    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

    PMID:23825951

    Open questions at the time
    • Precise RNA elements and binding geometry not yet mapped
    • Extent of host splicing effects unaddressed
  4. 2015 Medium

    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

    PMID:25619834

    Open questions at the time
    • Single lab
    • Whether IVNS1ABP itself acts as a functional E3 adaptor elsewhere not resolved here
  5. 2018 High

    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

    PMID:29921878

    Open questions at the time
    • Functional consequence of host mis-splicing for infection not fully defined
    • How the BTB-kelch architecture supports RNA-site occupancy unclear
  6. 2024 Medium

    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

    PMID:39384042

    Open questions at the time
    • Single lab
    • Stoichiometry and timing of the NS1/IVNS1ABP/NXF1 hand-off at the pore not fully resolved
  7. 2024 Medium

    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)

    Open questions at the time
    • 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
  8. 2026 High

    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

    PMID:41857046

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1 GO:0008092 cytoskeletal protein binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005654 nucleoplasm 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 1
Partners
ACTINENO1HNRNP A1HNRNP KKLHL20NS1NXF1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. 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 of virology High 9696811
2013 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. Proteomics (co-IP/MS), formaldehyde and UV cross-linking, siRNA knockdown, RT-PCR splicing assays, Western blot, virus replication assays PLoS pathogens High 23825951
2007 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. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, cotransfection/reporter assays, RT-PCR for endogenous c-Myc mRNA Biochimica et biophysica acta Medium 17996313
2018 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. RNA immunoprecipitation, CLIP, mutagenesis of RNA binding sites, splicing assays, virus replication assays, RNA-seq Nature communications High 29921878
2024 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. Co-immunoprecipitation, competition binding assays, RNA immunoprecipitation, nuclear export assays, cell biological imaging The Journal of biological chemistry Medium 39384042
2015 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. Co-immunoprecipitation, ubiquitination assays, mutagenesis, in vitro binding, in vivo metastasis models, cell migration/invasion assays Oncogene Medium 25619834
2026 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. Exome sequencing, iPSC generation and differentiation, cerebral organoids, cytokinesis assays, DNA damage assays, senescence assays, co-immunoprecipitation/binding assays for actin interaction, molecular profiling Nature communications High 41857046
2024 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. Patient-derived iPSC models, ubiquitome mass spectrometry, isogenic correction, zebrafish knockout, motor neuron differentiation, lysosomal function assays bioRxivpreprint Medium
2024 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. Co-immunoprecipitation, actin polymerization assays, live cell imaging of cytokinesis, senescence markers, isogenic iPSC-derived NPCs bioRxivpreprint Medium
2018 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. Transient transfection (overexpression and knockdown), Western blot for c-Myc, MTT proliferation assay, flow cytometry for apoptosis Zhonghua zhong liu za zhi [Chinese journal of oncology] Low 29365413

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Possible interactions between the NS-1 protein and tumor necrosis factor alpha pathways in erythroid cell apoptosis induced by human parvovirus B19. Journal of virology 130 10482630
1988 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. Journal of virology 128 3339715
1989 A genome-linked copy of the NS-1 polypeptide is located on the outside of infectious parvovirus particles. Journal of virology 123 2527311
1998 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. Journal of virology 107 9696811
1988 Minute virus of mice non-structural protein NS-1 is necessary and sufficient for trans-activation of the viral P39 promoter. The Journal of general virology 102 3171551
1990 NS-1 and NS-2 proteins may act synergistically in the cytopathogenicity of parvovirus MVMp. Virology 96 2137660
2013 Cellular RNA binding proteins NS1-BP and hnRNP K regulate influenza A virus RNA splicing. PLoS pathogens 83 23825951
1992 Terminal regions of the NS-1 protein of the parvovirus minute virus of mice are involved in cytotoxicity and promoter trans inhibition. Journal of virology 79 1388209
1975 Biochemically differentiated mouse glial lines carrying a nervous system specific cell surface antigen (NS-1). Proceedings of the National Academy of Sciences of the United States of America 77 168583
2018 Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing. Nature communications 70 29921878
2018 Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling. Viruses 70 30558248
1994 Mutations in the NTP-binding motif of minute virus of mice (MVM) NS-1 protein uncouple ATPase and DNA helicase functions. The Journal of biological chemistry 68 8106366
1988 Generation and characterization of a temperature-sensitive mutation in the NS-1 gene of the autonomous parvovirus minute virus of mice. Journal of virology 67 2969054
1995 Antibodies to parvovirus B19 NS-1 protein in infected individuals. The Journal of general virology 66 7534811
1995 Transcriptional activation by the parvoviral nonstructural protein NS-1 is mediated via a direct interaction with Sp1. Molecular and cellular biology 63 7799962
1974 NS-1 (nervous system antigen-1), a glial-cell-specific antigenic component of the surface membrane. Proceedings of the National Academy of Sciences of the United States of America 62 4134760
1999 Detection of porcine parvovirus DNA by the polymerase chain reaction assay using primers to the highly conserved nonstructural protein gene, NS-1. Journal of virological methods 60 10204709
1994 Targeting of promoters for trans activation by a carboxy-terminal domain of the NS-1 protein of the parvovirus minute virus of mice. Journal of virology 58 7966588
1986 The NS-1 polypeptide of the autonomous parvovirus MVM is a nuclear phosphoprotein. Virus research 48 3739422
2001 High-level expression of recombinant dengue viral NS-1 protein and its potential use as a diagnostic antigen. Journal of medical virology 47 11596093
1989 Enhanced transcription of the 78,000-dalton glucose-regulated protein (GRP78) gene and association of GRP78 with immunoglobulin light chains in a nonsecreting B-cell myeloma line (NS-1). Molecular and cellular biology 47 2501663
1991 NS 1 gene sequences from eight dengue-2 viruses and their evolutionary relationships with other dengue-2 viruses. Archives of virology 41 1829885
2007 The kelch protein NS1-BP interacts with alpha-enolase/MBP-1 and is involved in c-Myc gene transcriptional control. Biochimica et biophysica acta 37 17996313
1995 Purification and characterization of the major nonstructural protein (NS-1) of Aleutian mink disease parvovirus. Journal of virology 35 7853520
1988 Functional and antigenic domains of the dengue-2 virus nonstructural glycoprotein NS-1. Virology 34 2964755
2015 KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. Oncogene 33 25619834
2002 Biochemical characterization of Junonia coenia densovirus nonstructural protein NS-1. Journal of virology 28 11739698
1995 Transcriptional inhibition of the parvovirus minute virus of mice by constitutive expression of an antisense RNA targeted against the NS-1 transactivator protein. Virology 25 7831812
1984 A novel 6:10 chromosomal translocation in the murine plasmacytoma NS-1. Nature 25 6420709
1995 Involvement of PIM-1 in DNA fragmentation in mouse NS-1-derived cells. Biochemical and biophysical research communications 19 7487989
1989 An alternative method for the isolation of NS-1 hybridomas using cholesterol auxotrophy of NS-1 mouse myeloma cells. In vitro cellular & developmental biology : journal of the Tissue Culture Association 18 2732203
1992 Characterization of linker insertion and point mutations in the NS-1 gene of minute virus of mice: effects on DNA replication and transcriptional activation functions of NS-1. Virology 17 1533078
1984 Cholesterol requirement of NS-1 mouse myeloma cells for growth in serum-free medium. Molecular biology & medicine 17 6533417
1986 Biochemical characterization of the cholesterol-dependent growth of the NS-1 mouse myeloma cell line. Experimental cell research 16 3943557
1987 Expression of the 6C3 antigen on murine hematopoietic neoplasms. Association with expression of abl, ras, fes, src, erbB, and Cas NS-1 oncogenes but not with myc. The Journal of experimental medicine 15 3493323
1993 Mutational analysis of conserved tyrosines in the NS-1 protein of the parvovirus minute virus of mice. Virology 14 8503171
2019 Involvement of CHOP in activin A‑induced myeloma NS‑1 cell apoptosis. Oncology reports 13 31638256
1987 Detection of bovine parvovirus proteins homologous to the nonstructural NS-1 proteins of other autonomous parvoviruses. Journal of virology 13 2959794
1993 Spontaneous apoptosis in NS-1 myeloma cultures: effects of cell density, conditioned medium and acid pH. Immunobiology 12 8406554
2018 Comparative Evaluation of Indirect Immunofluorescence and NS-1-Based ELISA to Determine Zika Virus-Specific IgM. Viruses 10 30029548
2024 Cellular NS1-BP protein interacts with the mRNA export receptor NXF1 to mediate nuclear export of influenza virus M mRNAs. The Journal of biological chemistry 9 39384042
2021 Iocasia fonsfrigidae NS-1 gen. nov., sp. nov., a Novel Deep-Sea Bacterium Possessing Diverse Carbohydrate Metabolic Pathways. Frontiers in microbiology 9 34899621
1993 Inhibition of heterologous DNA replication by the MVMp nonstructural NS-1 protein: identification of a target sequence. Virology 8 8249286
2013 The role of anti-dengue virus NS-1 and anti-protein disulfide isomerase antibodies on platelet aggregation in secondary dengue infection. Acta medica Indonesiana 7 23585408
2012 Cloning and sequencing of the light chain variable region from NS-1 myeloma. Oncology letters 7 22783396
1987 Sterol depletion reduces receptor-mediated low-density lipoprotein binding in NS-1 mouse myeloma cells. Experimental cell research 7 3622637
2012 NS-1: a novel partial peroxisome proliferator-activated receptor γ agonist to improve insulin sensitivity and metabolic profile. European journal of pharmacology 6 22484334
1993 Sequence of the NS 1 gene of the K 23 isolate of tick-borne encephalitis virus and identification of conserved motifs. Archives of virology 6 8470955
2023 Biodegradation of Phenol Using the Indigenous Rhodococcus pyridinivorans Strain PDB9T NS-1 Immobilized in Calcium Alginate Beads. Applied biochemistry and biotechnology 4 37126112
1997 Deletion of the κ genes from mouse hybridomas established with NS-1 myelomas. Cytotechnology 4 22358764
2018 An efficient production of hybrid recombinant protein comprising non-structural proteins (NS 1 & NS 3) of bluetongue virus in prokaryotic expression system. Protein expression and purification 3 30217599
2025 Unveiling the diagnostic and causal role of hyperlipidemia- and lipophagy-associated genes PLAUR, IVNS1ABP, and QKI in acute myocardial infarction. International journal of cardiology 2 40782973
2008 The significance of arginase I administration on the survival of mice bearing NS-1 myeloma cells. The Journal of surgical research 2 18394650
1997 A preliminary analysis of antineoplastic activity of parvovirus MVMp NS-1 proteins. Cell research 2 9444400
2009 Expression, purification, and characterization of recombinant NS-1, the porcine parvovirus non-structural protein. Journal of virological methods 1 19101593
1993 Expression of the non-structural proteins of parvovirus MVMp from recombinant retroviruses: predominant role of the parvoviral NS-1 product in host cell disturbance. Research in virology 1 8140289
1993 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. Archives of virology 1 8347083
2026 IVNS1ABP mutation drives cellular senescence in newly identified progeroid neuropathy. Nature communications 0 41857046
2018 [Clinical significance of NS1-BP expression in esophageal squamous cell carcinoma]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 0 29365413
2003 [Establishment and identification of recombinant NS-1 cell strain that stably expresses chimeric HBc containing HBV multiepitope short peptides]. Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA 0 14625180
2001 [Antitumor Activities of KRN7000 in NS-1 Myeloma-Bearing Mice]. Zhongguo shi yan xue ye xue za zhi 0 12578576

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