{"gene":"CTNNBL1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2008,"finding":"CTNNBL1 physically interacts with AID (activation-induced deaminase) as identified by yeast two-hybrid and co-immunoprecipitation assays. AID mutants that disrupt CTNNBL1 interaction show severely diminished somatic hypermutation and class switch recombination. Targeted inactivation of CTNNBL1 in DT40 B cells also considerably diminishes IgV diversification. CTNNBL1 associates with the Prp19 complex of the spliceosome via its CDC5L component.","method":"Yeast two-hybrid, co-immunoprecipitation, targeted gene inactivation in DT40 cells, functional hypermutation/CSR assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus yeast two-hybrid plus genetic loss-of-function with defined functional readouts (hypermutation, class switching, IgV diversification), multiple orthogonal methods in a single rigorous study","pmids":["18722174"],"is_preprint":false},{"year":2011,"finding":"CTNNBL1 is a novel NLS (nuclear localization sequence)-binding protein distinct from karyopherin-α family members. It binds the NLS of the CDC5L component of the Prp19 complex and also interacts with the NLS of splicing factor Prp31. NLS binding is mediated by the CTNNBL1 armadillo (ARM) domain. The CTNNBL1/AID interaction depends on amino acids forming the AID conformational NLS, and CTNNBL1-deficient cells show a partial defect in AID nuclear accumulation. The CTNNBL1 N-terminal region itself binds karyopherin-α (rather than karyopherin-β), suggesting a role divergent from canonical nuclear transport.","method":"Co-immunoprecipitation, direct binding assays, mutational analysis of NLS residues, cellular localization studies in CTNNBL1-deficient cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, localization in deficient cells) in a single focused mechanistic study establishing a novel NLS-binding function","pmids":["21385873"],"is_preprint":false},{"year":2010,"finding":"CTNNBL1 is dispensable for Ig class switch recombination (CSR) in mouse CH12F3 cells; disruption of both CTNNBL1 alleles by gene targeting yielded normal CSR levels, indicating the CSR defect of AID mutants that fail to bind CTNNBL1 is not due to loss of CTNNBL1-dependent CSR function per se.","method":"Gene targeting (homologous recombination) to generate CTNNBL1-null CH12F3 cells, CSR assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gene knockout with defined functional readout (CSR), single lab, negative finding that is mechanistically informative","pmids":["20585033"],"is_preprint":false},{"year":2015,"finding":"CTNNBL1 facilitates the association of CWC15 with CDC5L within the Prp19 spliceosomal complex, acting as a chaperone for complex integrity. In vitro, CTNNBL1 enhances CWC15–CDC5L association; there is an overlapping binding region on CDC5L for CTNNBL1 and CWC15, suggesting they can exchange places. In vivo, CTNNBL1 deficiency reduces steady-state levels of the Prp19 complex and impairs CWC15–CDC5L interaction, leading to delayed initiation of cell division.","method":"Amine crosslinking and hydrogen-deuterium exchange coupled to mass spectrometry, in vitro association assays, in vivo CTNNBL1 knockdown/deficiency with Prp19 complex quantification and cell division assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural/crosslinking MS plus in vitro reconstitution plus in vivo genetic deficiency with multiple orthogonal functional readouts","pmids":["26130721"],"is_preprint":false},{"year":2003,"finding":"CTNNBL1 encodes a 563-amino-acid armadillo (ARM) motif-containing nuclear protein. Transient overexpression in CHO cells localizes to the nucleus and induces apoptosis; a carboxy-terminal fragment induces apoptosis at a higher rate than full-length, mapping apoptosis-inducing activity to the C-terminal region. The gene contains a minor-class AT–AC intron (intron 4).","method":"cDNA cloning, transfection of CHO cells with full-length and truncation constructs, subcellular localization by imaging, cell death quantification","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transfection-based localization and apoptosis assay with truncation mapping, single lab, two orthogonal readouts","pmids":["12659813"],"is_preprint":false},{"year":2017,"finding":"CTNNBL1 is upregulated in high-grade serous ovarian carcinoma and promotes proliferation and invasion of ovarian cancer cells in vitro. Transcriptome analysis revealed that CTNNBL1 regulates multiple splicing events and gene expression, including alternative splicing of IFI16 and FOXM1.","method":"siRNA knockdown in ovarian cancer cell lines, proliferation and invasion assays, RNA-seq transcriptome analysis of splicing events","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — knockdown with defined cellular phenotypes and transcriptome-level splicing readout, single lab","pmids":["28501461"],"is_preprint":false}],"current_model":"CTNNBL1 is a nuclear armadillo (ARM) domain-containing protein that functions as a selective NLS-binding protein and spliceosomal chaperone: it associates with the Prp19 complex by binding the NLS of CDC5L and also interacts with Prp31, maintains the abundance and integrity of the Prp19 complex by facilitating CWC15–CDC5L association, and separately binds the conformational NLS of the antibody-diversifying enzyme AID, partially promoting AID nuclear accumulation and efficient immunoglobulin gene hypermutation and gene conversion, though it is dispensable for class switch recombination in mammalian B cells."},"narrative":{"mechanistic_narrative":"CTNNBL1 is a nuclear armadillo (ARM) domain-containing protein that operates as a selective NLS-binding adaptor coupling nuclear import recognition to spliceosome integrity [PMID:21385873, PMID:26130721]. Distinct from karyopherin-α family transport receptors, its ARM domain binds the nuclear localization sequences of the CDC5L and Prp31 components of the Prp19 spliceosomal complex, and it stabilizes complex architecture by facilitating CWC15–CDC5L association; loss of CTNNBL1 lowers steady-state Prp19 complex levels and delays cell division [PMID:21385873, PMID:26130721]. Through its associated splicing activity it governs alternative splicing of specific transcripts and supports cell proliferation and invasion [PMID:28501461]. Separately, CTNNBL1 binds the conformational NLS of the antibody-diversifying enzyme AID, partially promoting AID nuclear accumulation and enabling efficient immunoglobulin hypermutation and IgV gene diversification, while being dispensable for class switch recombination [PMID:18722174, PMID:21385873, PMID:20585033].","teleology":[{"year":2003,"claim":"Initial characterization established CTNNBL1 as a nuclear ARM-motif protein and mapped an apoptosis-inducing activity to its C-terminus, providing the first functional foothold for an otherwise uncharacterized gene.","evidence":"cDNA cloning and transfection of full-length and truncation constructs in CHO cells with imaging and cell-death quantification","pmids":["12659813"],"confidence":"Medium","gaps":["Overexpression apoptosis phenotype not linked to a physiological pathway","No endogenous binding partners identified","ARM domain function undefined at this stage"]},{"year":2008,"claim":"Identifying CTNNBL1 as a physical partner of AID and of the Prp19 spliceosomal complex connected the protein simultaneously to antibody diversification and to RNA splicing machinery.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, and targeted gene inactivation in DT40 B cells with hypermutation/CSR/IgV diversification assays","pmids":["18722174"],"confidence":"High","gaps":["Mechanism by which CTNNBL1 promotes AID activity not resolved","Whether the splicing and AID functions are mechanistically linked unclear"]},{"year":2010,"claim":"A clean CTNNBL1-null B-cell knockout showed normal class switch recombination, separating CTNNBL1's contribution from a general requirement for CSR and refining which AID functions depend on it.","evidence":"Gene targeting to generate CTNNBL1-null CH12F3 cells with CSR assay","pmids":["20585033"],"confidence":"Medium","gaps":["Does not explain the CSR defect of AID mutants that fail to bind CTNNBL1","Hypermutation phenotype in this system not addressed"]},{"year":2011,"claim":"Defining CTNNBL1 as an NLS-binding protein distinct from karyopherins explained both its AID and spliceosome associations as recognition of nuclear localization sequences via its ARM domain.","evidence":"Co-immunoprecipitation, direct binding assays, NLS-residue mutagenesis, and localization in CTNNBL1-deficient cells","pmids":["21385873"],"confidence":"High","gaps":["AID nuclear accumulation defect only partial, implying redundant import routes","Functional consequence of Prp31 NLS binding not established"]},{"year":2015,"claim":"Mapping CTNNBL1 as a chaperone that promotes CWC15–CDC5L assembly established a concrete mechanism for how it maintains Prp19 complex integrity and supports timely cell division.","evidence":"Crosslinking and hydrogen-deuterium exchange mass spectrometry, in vitro association assays, and in vivo CTNNBL1 deficiency with complex quantification and cell division assays","pmids":["26130721"],"confidence":"High","gaps":["Structural basis of the CTNNBL1/CWC15 exchange on CDC5L not solved at atomic resolution","Direct link between this chaperone role and splicing catalysis not shown"]},{"year":2017,"claim":"Linking CTNNBL1 to control of specific alternative splicing events and to proliferation/invasion phenotypes connected its spliceosomal role to a cancer-relevant cellular output.","evidence":"siRNA knockdown in ovarian cancer cell lines with proliferation/invasion assays and RNA-seq splicing analysis (IFI16, FOXM1)","pmids":["28501461"],"confidence":"Medium","gaps":["Whether splicing changes are direct CTNNBL1 targets vs secondary to Prp19 destabilization unclear","Causal contribution of individual splicing events to the proliferation phenotype not dissected"]},{"year":null,"claim":"How CTNNBL1's NLS-recognition activity is integrated with karyopherin-dependent import and whether its spliceosomal chaperone role mechanistically underlies its support of AID-driven hypermutation remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CTNNBL1 bound to a conformational NLS","Unknown whether AID and spliceosome functions share a common biochemical basis","Physiological in vivo role beyond cell-line systems undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]}],"complexes":["Prp19 complex"],"partners":["CDC5L","CWC15","PRPF31","AICDA","KPNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WYA6","full_name":"Beta-catenin-like protein 1","aliases":["Nuclear-associated protein","NAP","Testis development protein NYD-SP19"],"length_aa":563,"mass_kda":65.2,"function":"Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. Participates in AID/AICDA-mediated somatic hypermutation (SHM) and class-switch recombination (CSR), 2 processes resulting in the production of high-affinity, mutated isotype-switched antibodies (PubMed:32484799)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8WYA6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CTNNBL1","classification":"Common Essential","n_dependent_lines":1140,"n_total_lines":1208,"dependency_fraction":0.9437086092715232},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132792","cell_line_id":"CID001025","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"CWC15","stoichiometry":10.0},{"gene":"PRPF19","stoichiometry":10.0},{"gene":"CDC5L","stoichiometry":10.0},{"gene":"PLRG1","stoichiometry":10.0},{"gene":"BCAS2","stoichiometry":4.0},{"gene":"CRNKL1","stoichiometry":0.2},{"gene":"ISY1","stoichiometry":0.2},{"gene":"PPIE","stoichiometry":0.2},{"gene":"ZNF830","stoichiometry":0.2},{"gene":"XAB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001025","total_profiled":1310},"omim":[{"mim_id":"621501","title":"CWC15, SPLICEOSOME-ASSOCIATED PROTEIN; CWC15","url":"https://www.omim.org/entry/621501"},{"mim_id":"619846","title":"IMMUNODEFICIENCY 99 WITH HYPOGAMMAGLOBULINEMIA AND AUTOIMMUNE CYTOPENIAS; IMD99","url":"https://www.omim.org/entry/619846"},{"mim_id":"611537","title":"CATENIN, BETA-LIKE, 1; CTNNBL1","url":"https://www.omim.org/entry/611537"},{"mim_id":"602868","title":"CELL DIVISION CYCLE 5-LIKE; CDC5L","url":"https://www.omim.org/entry/602868"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CTNNBL1"},"hgnc":{"alias_symbol":["FLJ21108","P14L","P14","NAP","NYD-SP19"],"prev_symbol":["C20orf33"]},"alphafold":{"accession":"Q8WYA6","domains":[{"cath_id":"-","chopping":"440-561","consensus_level":"high","plddt":91.8805,"start":440,"end":561},{"cath_id":"1.20.930","chopping":"79-229","consensus_level":"medium","plddt":96.8011,"start":79,"end":229}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WYA6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WYA6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WYA6-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTNNBL1","jax_strain_url":"https://www.jax.org/strain/search?query=CTNNBL1"},"sequence":{"accession":"Q8WYA6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WYA6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WYA6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WYA6"}},"corpus_meta":[{"pmid":"1510812","id":"PMC_1510812","title":"Endothelial 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An immunocytochemical and fluorescent in situ hybridization study.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2404062","citation_count":78,"is_preprint":false},{"pmid":"10945988","id":"PMC_10945988","title":"Association of immature hypophosphorylated protein kinase cepsilon with an anchoring protein CG-NAP.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10945988","citation_count":76,"is_preprint":false},{"pmid":"9108140","id":"PMC_9108140","title":"Brassica nap cytoplasmic male sterility is associated with expression of a mtDNA region containing a chimeric gene similar to the pol CMS-associated orf224 gene.","date":"1997","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9108140","citation_count":76,"is_preprint":false},{"pmid":"28115743","id":"PMC_28115743","title":"ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy.","date":"2017","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28115743","citation_count":71,"is_preprint":false},{"pmid":"24430487","id":"PMC_24430487","title":"Deep-sea hydrothermal vent Epsilonproteobacteria encode a conserved and widespread nitrate reduction pathway (Nap).","date":"2014","source":"The ISME journal","url":"https://pubmed.ncbi.nlm.nih.gov/24430487","citation_count":63,"is_preprint":false},{"pmid":"15665412","id":"PMC_15665412","title":"The femtomolar-acting NAP interacts with microtubules: Novel aspects of astrocyte protection.","date":"2004","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/15665412","citation_count":63,"is_preprint":false},{"pmid":"17371778","id":"PMC_17371778","title":"The neutrophil-activating Dps protein of Helicobacter pylori, HP-NAP, adopts a mechanism different from Escherichia coli Dps to bind and condense DNA.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17371778","citation_count":63,"is_preprint":false},{"pmid":"18220512","id":"PMC_18220512","title":"NAP, a neuroprotective drug candidate in clinical trials, stimulates microtubule assembly in the living cell.","date":"2007","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/18220512","citation_count":63,"is_preprint":false},{"pmid":"15800376","id":"PMC_15800376","title":"Activity-dependent neurotrophic factor-9 and NAP promote neurite outgrowth in rat hippocampal and cortical cultures.","date":"2005","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/15800376","citation_count":60,"is_preprint":false},{"pmid":"18414890","id":"PMC_18414890","title":"The neuropeptide NAP provides neuroprotection against retinal ganglion cell damage after retinal ischemia and optic nerve crush.","date":"2008","source":"Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie","url":"https://pubmed.ncbi.nlm.nih.gov/18414890","citation_count":60,"is_preprint":false},{"pmid":"7504015","id":"PMC_7504015","title":"cDNA cloning and expression of guinea pig neutrophil attractant protein-1 (NAP-1). 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AID mutants that disrupt CTNNBL1 interaction show severely diminished somatic hypermutation and class switch recombination. Targeted inactivation of CTNNBL1 in DT40 B cells also considerably diminishes IgV diversification. CTNNBL1 associates with the Prp19 complex of the spliceosome via its CDC5L component.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, targeted gene inactivation in DT40 cells, functional hypermutation/CSR assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus yeast two-hybrid plus genetic loss-of-function with defined functional readouts (hypermutation, class switching, IgV diversification), multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18722174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTNNBL1 is a novel NLS (nuclear localization sequence)-binding protein distinct from karyopherin-α family members. It binds the NLS of the CDC5L component of the Prp19 complex and also interacts with the NLS of splicing factor Prp31. NLS binding is mediated by the CTNNBL1 armadillo (ARM) domain. The CTNNBL1/AID interaction depends on amino acids forming the AID conformational NLS, and CTNNBL1-deficient cells show a partial defect in AID nuclear accumulation. The CTNNBL1 N-terminal region itself binds karyopherin-α (rather than karyopherin-β), suggesting a role divergent from canonical nuclear transport.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, mutational analysis of NLS residues, cellular localization studies in CTNNBL1-deficient cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, localization in deficient cells) in a single focused mechanistic study establishing a novel NLS-binding function\",\n      \"pmids\": [\"21385873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CTNNBL1 is dispensable for Ig class switch recombination (CSR) in mouse CH12F3 cells; disruption of both CTNNBL1 alleles by gene targeting yielded normal CSR levels, indicating the CSR defect of AID mutants that fail to bind CTNNBL1 is not due to loss of CTNNBL1-dependent CSR function per se.\",\n      \"method\": \"Gene targeting (homologous recombination) to generate CTNNBL1-null CH12F3 cells, CSR assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gene knockout with defined functional readout (CSR), single lab, negative finding that is mechanistically informative\",\n      \"pmids\": [\"20585033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTNNBL1 facilitates the association of CWC15 with CDC5L within the Prp19 spliceosomal complex, acting as a chaperone for complex integrity. In vitro, CTNNBL1 enhances CWC15–CDC5L association; there is an overlapping binding region on CDC5L for CTNNBL1 and CWC15, suggesting they can exchange places. In vivo, CTNNBL1 deficiency reduces steady-state levels of the Prp19 complex and impairs CWC15–CDC5L interaction, leading to delayed initiation of cell division.\",\n      \"method\": \"Amine crosslinking and hydrogen-deuterium exchange coupled to mass spectrometry, in vitro association assays, in vivo CTNNBL1 knockdown/deficiency with Prp19 complex quantification and cell division assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural/crosslinking MS plus in vitro reconstitution plus in vivo genetic deficiency with multiple orthogonal functional readouts\",\n      \"pmids\": [\"26130721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CTNNBL1 encodes a 563-amino-acid armadillo (ARM) motif-containing nuclear protein. Transient overexpression in CHO cells localizes to the nucleus and induces apoptosis; a carboxy-terminal fragment induces apoptosis at a higher rate than full-length, mapping apoptosis-inducing activity to the C-terminal region. The gene contains a minor-class AT–AC intron (intron 4).\",\n      \"method\": \"cDNA cloning, transfection of CHO cells with full-length and truncation constructs, subcellular localization by imaging, cell death quantification\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transfection-based localization and apoptosis assay with truncation mapping, single lab, two orthogonal readouts\",\n      \"pmids\": [\"12659813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTNNBL1 is upregulated in high-grade serous ovarian carcinoma and promotes proliferation and invasion of ovarian cancer cells in vitro. Transcriptome analysis revealed that CTNNBL1 regulates multiple splicing events and gene expression, including alternative splicing of IFI16 and FOXM1.\",\n      \"method\": \"siRNA knockdown in ovarian cancer cell lines, proliferation and invasion assays, RNA-seq transcriptome analysis of splicing events\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — knockdown with defined cellular phenotypes and transcriptome-level splicing readout, single lab\",\n      \"pmids\": [\"28501461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTNNBL1 is a nuclear armadillo (ARM) domain-containing protein that functions as a selective NLS-binding protein and spliceosomal chaperone: it associates with the Prp19 complex by binding the NLS of CDC5L and also interacts with Prp31, maintains the abundance and integrity of the Prp19 complex by facilitating CWC15–CDC5L association, and separately binds the conformational NLS of the antibody-diversifying enzyme AID, partially promoting AID nuclear accumulation and efficient immunoglobulin gene hypermutation and gene conversion, though it is dispensable for class switch recombination in mammalian B cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTNNBL1 is a nuclear armadillo (ARM) domain-containing protein that operates as a selective NLS-binding adaptor coupling nuclear import recognition to spliceosome integrity [#1, #3]. Distinct from karyopherin-\\u03b1 family transport receptors, its ARM domain binds the nuclear localization sequences of the CDC5L and Prp31 components of the Prp19 spliceosomal complex, and it stabilizes complex architecture by facilitating CWC15\\u2013CDC5L association; loss of CTNNBL1 lowers steady-state Prp19 complex levels and delays cell division [#1, #3]. Through its associated splicing activity it governs alternative splicing of specific transcripts and supports cell proliferation and invasion [#5]. Separately, CTNNBL1 binds the conformational NLS of the antibody-diversifying enzyme AID, partially promoting AID nuclear accumulation and enabling efficient immunoglobulin hypermutation and IgV gene diversification, while being dispensable for class switch recombination [#0, #1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Initial characterization established CTNNBL1 as a nuclear ARM-motif protein and mapped an apoptosis-inducing activity to its C-terminus, providing the first functional foothold for an otherwise uncharacterized gene.\",\n      \"evidence\": \"cDNA cloning and transfection of full-length and truncation constructs in CHO cells with imaging and cell-death quantification\",\n      \"pmids\": [\"12659813\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Overexpression apoptosis phenotype not linked to a physiological pathway\", \"No endogenous binding partners identified\", \"ARM domain function undefined at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying CTNNBL1 as a physical partner of AID and of the Prp19 spliceosomal complex connected the protein simultaneously to antibody diversification and to RNA splicing machinery.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, and targeted gene inactivation in DT40 B cells with hypermutation/CSR/IgV diversification assays\",\n      \"pmids\": [\"18722174\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which CTNNBL1 promotes AID activity not resolved\", \"Whether the splicing and AID functions are mechanistically linked unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A clean CTNNBL1-null B-cell knockout showed normal class switch recombination, separating CTNNBL1's contribution from a general requirement for CSR and refining which AID functions depend on it.\",\n      \"evidence\": \"Gene targeting to generate CTNNBL1-null CH12F3 cells with CSR assay\",\n      \"pmids\": [\"20585033\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not explain the CSR defect of AID mutants that fail to bind CTNNBL1\", \"Hypermutation phenotype in this system not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining CTNNBL1 as an NLS-binding protein distinct from karyopherins explained both its AID and spliceosome associations as recognition of nuclear localization sequences via its ARM domain.\",\n      \"evidence\": \"Co-immunoprecipitation, direct binding assays, NLS-residue mutagenesis, and localization in CTNNBL1-deficient cells\",\n      \"pmids\": [\"21385873\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"AID nuclear accumulation defect only partial, implying redundant import routes\", \"Functional consequence of Prp31 NLS binding not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping CTNNBL1 as a chaperone that promotes CWC15\\u2013CDC5L assembly established a concrete mechanism for how it maintains Prp19 complex integrity and supports timely cell division.\",\n      \"evidence\": \"Crosslinking and hydrogen-deuterium exchange mass spectrometry, in vitro association assays, and in vivo CTNNBL1 deficiency with complex quantification and cell division assays\",\n      \"pmids\": [\"26130721\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of the CTNNBL1/CWC15 exchange on CDC5L not solved at atomic resolution\", \"Direct link between this chaperone role and splicing catalysis not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking CTNNBL1 to control of specific alternative splicing events and to proliferation/invasion phenotypes connected its spliceosomal role to a cancer-relevant cellular output.\",\n      \"evidence\": \"siRNA knockdown in ovarian cancer cell lines with proliferation/invasion assays and RNA-seq splicing analysis (IFI16, FOXM1)\",\n      \"pmids\": [\"28501461\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether splicing changes are direct CTNNBL1 targets vs secondary to Prp19 destabilization unclear\", \"Causal contribution of individual splicing events to the proliferation phenotype not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CTNNBL1's NLS-recognition activity is integrated with karyopherin-dependent import and whether its spliceosomal chaperone role mechanistically underlies its support of AID-driven hypermutation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of CTNNBL1 bound to a conformational NLS\", \"Unknown whether AID and spliceosome functions share a common biochemical basis\", \"Physiological in vivo role beyond cell-line systems undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"Prp19 complex\"],\n    \"partners\": [\"CDC5L\", \"CWC15\", \"PRPF31\", \"AICDA\", \"KPNA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}