{"gene":"UNC119B","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2011,"finding":"UNC119B (but not UNC119A) functions as a myristoyl-binding chaperone that captures myristoylated NPHP3 via conserved hydrophobic phenylalanines in a β-sandwich fold; ARL3-GTP releases the myristoylated cargo from UNC119B; and ARL3, UNC119B, and the ARL3 GAP RP2 are all required for NPHP3 ciliary targeting. UNC119B myristoyl-binding activity is required for this function.","method":"Proteomic pulldown, directed mutagenesis of structural model, structural modeling of UNC119-myristate complex, siRNA knockdown in IMCD3 cells with ciliary localization readout, genetic requirement established by co-depletion","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural modeling with mutagenesis, biochemical interaction mapping, and functional knockdown with specific ciliary targeting readout, all in a single rigorous study","pmids":["22085962"],"is_preprint":false},{"year":2012,"finding":"UNC119B functions as a lipid-binding chaperone with specificity for myristoylated proteins; UNC119B knockdown in IMCD3 cells prevents trafficking of myristoylated NPHP3 to cilia, establishing a direct role in ciliary targeting of myristoylated cargo.","method":"siRNA knockdown with ciliary localization readout; biochemical characterization of lipid-binding specificity","journal":"Vision research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review consolidating findings from multiple labs including knockdown data; functional conclusion replicated from primary study (PMID:22085962)","pmids":["23000199"],"is_preprint":false},{"year":2016,"finding":"UNC119B binds myristoylated cargo peptides (GNAT1, NPHP3, Cystin1, RP2, Src) with affinities ranging from subnanomolar to micromolar; ciliary proteins bind with high affinity and are exclusively released by ARL3·GppNHp, whereas low-affinity cargo can be released by both ARL2·GppNHp and ARL3·GppNHp. X-ray structure of myristoylated NPHP3 peptide in complex with UNC119a revealed that residues at +2 and +3 positions relative to the myristoylated glycine determine binding affinity; swapping these residues between high- and low-affinity peptides reversed their affinities and partially mislocalized NPHP3.","method":"Fluorescence polarization binding assays, X-ray crystallography, site-directed mutagenesis, cellular mislocalization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structure, quantitative binding assays, and mutagenesis with functional validation in a single study","pmids":["27481943"],"is_preprint":false},{"year":2015,"finding":"UNC119B (and UNC119A) binds exclusively mono-N-myristoylated peptides but does not recognize doubly lipidated or S-isoprenylated C-terminal peptides, establishing lipid specificity of the chaperone.","method":"Synthetic lipid-modified peptide binding assays to purified chaperones (biochemical specificity profiling)","journal":"Chembiochem : a European journal of chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays with synthetic peptides, single lab, multiple cargo tested orthogonally","pmids":["26503308"],"is_preprint":false},{"year":2021,"finding":"Upregulation of UNC119B (in zebrafish unc119b and in urine-derived renal epithelial cells from human Joubert syndrome CEP290 patients) partially rescues cilia defects caused by cep290 deficiency; ectopic expression of unc119b in cep290 morphant zebrafish rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects, placing UNC119B in the lipidated protein trafficking-to-cilia pathway downstream of or in parallel with CEP290.","method":"Morpholino knockdown rescue by ectopic expression in zebrafish, human patient cell analysis, genetic epistasis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment with specific cilia phenotype readout in zebrafish model, supported by human patient cell data, single lab","pmids":["34155518"],"is_preprint":false},{"year":2025,"finding":"UNC119B interacts with Rac1 and inhibits its insulin-stimulated activation, resulting in reduced GLUT4 translocation. The prenylated C-terminus of Rac1 and the small molecule C59 compete for the same binding site within UNC119B. Genetic knockdown or inhibition of UNC119B improves insulin sensitivity in rodent models of insulin resistance.","method":"Co-immunoprecipitation, in vitro binding competition assay, genetic knockdown/overexpression in cell lines, rodent models of insulin resistance with GLUT4 translocation and glucose homeostasis readouts","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction data, in vitro competition assay, and in vivo genetic manipulation with defined metabolic readout, single lab","pmids":["40754229"],"is_preprint":false},{"year":2025,"finding":"UNC119B is a protein interactor of PSKH1 kinase and activates PSKH1 catalytic activity via direct engagement of the kinase domain, identified as an allosteric activator.","method":"Biochemistry and mass spectrometry-based interactome analysis, kinase activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interactor identification with kinase activity assay, single study, single lab; preprint and peer-reviewed versions concordant","pmids":["39964718"],"is_preprint":false}],"current_model":"UNC119B is a myristoyl-binding chaperone that captures N-myristoylated cargo proteins (e.g., NPHP3, GNAT1, Cystin1) via a hydrophobic β-sandwich pocket with affinity determined by residues at the +2/+3 positions relative to the myristoylated glycine; ciliary delivery is completed when ARL3-GTP (but not ARL2-GTP for high-affinity cargo) displaces the cargo inside the cilium in a GTPase cycle involving the ARL3 GAP RP2, and UNC119B also inhibits Rac1 activation to suppress GLUT4 translocation and acts as an allosteric activator of PSKH1 kinase."},"narrative":{"mechanistic_narrative":"UNC119B is a myristoyl-binding chaperone that solubilizes and traffics N-myristoylated cargo proteins to the cilium [PMID:22085962]. It captures monomyristoylated cargo such as NPHP3, GNAT1, and Cystin1 within a hydrophobic β-sandwich pocket lined by conserved phenylalanines, binding only mono-N-myristoylated peptides and not doubly lipidated or isoprenylated termini [PMID:22085962, PMID:26503308]. Binding affinity ranges from subnanomolar to micromolar and is set by the residues at the +2 and +3 positions relative to the myristoylated glycine; swapping these residues reverses affinity and mislocalizes cargo [PMID:27481943]. Cargo release is governed by an ARL GTPase switch: high-affinity ciliary cargo is displaced specifically by ARL3-GTP, whereas low-affinity cargo can also be released by ARL2-GTP, and efficient ciliary targeting of NPHP3 requires both ARL3 and its GAP RP2 [PMID:22085962, PMID:27481943]. Consistent with a role in ciliary lipidated-protein trafficking, UNC119B expression partially rescues cilia defects caused by CEP290 deficiency in zebrafish and human patient cells [PMID:34155518]. Beyond cilia, UNC119B engages the prenylated C-terminus of Rac1 to inhibit insulin-stimulated Rac1 activation and GLUT4 translocation, with its loss improving insulin sensitivity in rodent models [PMID:40754229], and it acts as an allosteric activator of PSKH1 kinase through direct engagement of the kinase domain [PMID:39964718].","teleology":[{"year":2011,"claim":"Established that UNC119B, distinct from UNC119A, is a myristoyl-binding chaperone required for ciliary delivery of myristoylated cargo, answering how lipidated cargo such as NPHP3 reaches the cilium.","evidence":"Proteomic pulldown, structural modeling with mutagenesis of β-sandwich phenylalanines, and siRNA knockdown in IMCD3 cells with ciliary localization and ARL3-GTP release readouts","pmids":["22085962"],"confidence":"High","gaps":["Cargo repertoire beyond NPHP3 not defined","Atomic structure of UNC119B-myristate complex not determined in this study"]},{"year":2012,"claim":"Consolidated UNC119B as a lipid-binding chaperone with myristoyl specificity whose depletion blocks NPHP3 ciliary trafficking, reinforcing its direct trafficking role.","evidence":"siRNA knockdown with ciliary localization readout and biochemical lipid-binding characterization (review consolidation)","pmids":["23000199"],"confidence":"Medium","gaps":["Largely confirmatory of prior primary work","No new mechanistic detail on release step"]},{"year":2015,"claim":"Defined the lipid-recognition rule, showing the chaperone reads mono-N-myristoylation exclusively and rejects double-lipidated or isoprenylated termini.","evidence":"Binding assays of synthetic lipid-modified peptides to purified chaperone","pmids":["26503308"],"confidence":"Medium","gaps":["In vitro peptide assays only; cellular consequence of discrimination not tested","Single lab"]},{"year":2016,"claim":"Resolved how cargo affinity is encoded and how the ARL GTPase switch sorts cargo, explaining selective ARL3-GTP-dependent release of high-affinity ciliary cargo.","evidence":"Fluorescence polarization affinity measurements, X-ray crystallography of myristoylated NPHP3 peptide complex, and +2/+3 residue swap mutagenesis with cellular mislocalization assay","pmids":["27481943"],"confidence":"High","gaps":["Structure solved with UNC119a paralog rather than UNC119B","In vivo affinity thresholds for additional cargo not mapped"]},{"year":2021,"claim":"Placed UNC119B within the CEP290-dependent ciliary trafficking pathway by showing it can compensate for CEP290 loss.","evidence":"Morpholino knockdown rescue by ectopic unc119b expression in zebrafish and analysis of human Joubert syndrome CEP290 patient cells","pmids":["34155518"],"confidence":"Medium","gaps":["Epistatic order relative to CEP290 not fully resolved","Rescue only partial for photoreceptor defects"]},{"year":2025,"claim":"Extended UNC119B function beyond cilia, identifying it as a negative regulator of Rac1-driven GLUT4 translocation and insulin signaling.","evidence":"Co-immunoprecipitation, in vitro binding competition with the prenylated Rac1 C-terminus and compound C59, and genetic knockdown/overexpression in cells and rodent insulin-resistance models","pmids":["40754229"],"confidence":"Medium","gaps":["How prenyl-cargo binding reconciles with myristoyl specificity not explained","Single lab"]},{"year":2025,"claim":"Identified a kinase-regulatory role, with UNC119B acting as an allosteric activator of PSKH1.","evidence":"Mass spectrometry interactome analysis and kinase activity assays with direct kinase-domain engagement","pmids":["39964718"],"confidence":"Medium","gaps":["Structural basis of allosteric activation unknown","Physiological context of UNC119B-PSKH1 signaling undefined"]},{"year":null,"claim":"How UNC119B reconciles myristoyl-specific cargo capture with binding to a prenylated Rac1 terminus, and how its ciliary, metabolic, and kinase-regulatory functions are coordinated in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model spanning myristoyl and prenyl cargo","Tissue- and pathway-specific partitioning of functions not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["NPHP3","GNAT1","CYSTIN1","RP2","ARL3","RAC1","PSKH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NIH7","full_name":"Protein unc-119 homolog B","aliases":[],"length_aa":251,"mass_kda":28.1,"function":"Myristoyl-binding protein that acts as a cargo adapter: specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated NPHP3 and plays a key role in localization of NPHP3 to the primary cilium membrane. Does not bind all myristoylated proteins. Probably plays a role in trafficking proteins in photoreceptor cells","subcellular_location":"Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/A6NIH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UNC119B","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UNC119B","total_profiled":1310},"omim":[{"mim_id":"620513","title":"UNC119 LIPID-BINDING CHAPERONE B; UNC119B","url":"https://www.omim.org/entry/620513"},{"mim_id":"607408","title":"D-AMINO ACID OXIDASE ACTIVATOR; DAOA","url":"https://www.omim.org/entry/607408"},{"mim_id":"604011","title":"UNC119 LIPID-BINDING CHAPERONE; UNC119","url":"https://www.omim.org/entry/604011"},{"mim_id":"181500","title":"SCHIZOPHRENIA; SCZD","url":"https://www.omim.org/entry/181500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytokinetic bridge","reliability":"Uncertain"},{"location":"Mitotic spindle","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Flagellar centriole","reliability":"Uncertain"},{"location":"Annulus","reliability":"Uncertain"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UNC119B"},"hgnc":{"alias_symbol":["MGC5139","POC7B"],"prev_symbol":[]},"alphafold":{"accession":"A6NIH7","domains":[{"cath_id":"2.70.50.40","chopping":"56-116_137-245","consensus_level":"high","plddt":95.2967,"start":56,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NIH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NIH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NIH7-F1-predicted_aligned_error_v6.png","plddt_mean":79.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UNC119B","jax_strain_url":"https://www.jax.org/strain/search?query=UNC119B"},"sequence":{"accession":"A6NIH7","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NIH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NIH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NIH7"}},"corpus_meta":[{"pmid":"22085962","id":"PMC_22085962","title":"An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/22085962","citation_count":190,"is_preprint":false},{"pmid":"22291609","id":"PMC_22291609","title":"A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22291609","citation_count":130,"is_preprint":false},{"pmid":"23000199","id":"PMC_23000199","title":"Uncoordinated (UNC)119: coordinating the trafficking of myristoylated proteins.","date":"2012","source":"Vision research","url":"https://pubmed.ncbi.nlm.nih.gov/23000199","citation_count":57,"is_preprint":false},{"pmid":"27481943","id":"PMC_27481943","title":"Novel Biochemical and Structural Insights into the Interaction of Myristoylated Cargo with Unc119 Protein and Their Release by Arl2/3.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27481943","citation_count":41,"is_preprint":false},{"pmid":"37903971","id":"PMC_37903971","title":"Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37903971","citation_count":38,"is_preprint":false},{"pmid":"27911709","id":"PMC_27911709","title":"Shuttling and sorting lipid-modified cargo into the cilia.","date":"2016","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/27911709","citation_count":26,"is_preprint":false},{"pmid":"34155518","id":"PMC_34155518","title":"Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34155518","citation_count":23,"is_preprint":false},{"pmid":"26503308","id":"PMC_26503308","title":"Specificity of Lipoprotein Chaperones for the Characteristic Lipidated Structural Motifs of their Cognate Lipoproteins.","date":"2015","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/26503308","citation_count":18,"is_preprint":false},{"pmid":"36959629","id":"PMC_36959629","title":"DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight.","date":"2023","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/36959629","citation_count":12,"is_preprint":false},{"pmid":"27079236","id":"PMC_27079236","title":"Knockdown of unc119c results in visual impairment and early-onset retinal dystrophy in zebrafish.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27079236","citation_count":8,"is_preprint":false},{"pmid":"38303056","id":"PMC_38303056","title":"Identification of DNA methylation biomarkers for evaluating cardiovascular disease risk from epigenome profiles altered by low-dose ionizing radiation.","date":"2024","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/38303056","citation_count":4,"is_preprint":false},{"pmid":"29931788","id":"PMC_29931788","title":"UNC119 is a binding partner of tumor suppressor Ras-association domain family 6 and induces apoptosis and cell cycle arrest by MDM2 and p53.","date":"2018","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/29931788","citation_count":4,"is_preprint":false},{"pmid":"39964718","id":"PMC_39964718","title":"PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39964718","citation_count":3,"is_preprint":false},{"pmid":"40754229","id":"PMC_40754229","title":"Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue.","date":"2025","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40754229","citation_count":1,"is_preprint":false},{"pmid":"37164532","id":"PMC_37164532","title":"The challenge of dissecting gene function in model organisms: Tools to characterize genetic mutants and assess transcriptional adaptation in zebrafish.","date":"2023","source":"Methods in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37164532","citation_count":1,"is_preprint":false},{"pmid":"41530847","id":"PMC_41530847","title":"Smoking behaviour, altered DNA methylation, and heart failure risk: evidence from a prospective cohort and epigenetic Mendelian randomization study.","date":"2026","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/41530847","citation_count":0,"is_preprint":false},{"pmid":"31055152","id":"PMC_31055152","title":"Evolution and expression of the zebrafish unc119 paralogues indicates a conserved role in cilia.","date":"2019","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/31055152","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.20.619163","title":"PSKH1 kinase activity is differentially modulated via allosteric binding of Ca  <sup>2+</sup>  sensor proteins","date":"2024-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.20.619163","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11608,"output_tokens":1951,"usd":0.032044,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8853,"output_tokens":2633,"usd":0.055045,"stage2_stop_reason":"end_turn"},"total_usd":0.087089,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"UNC119B (but not UNC119A) functions as a myristoyl-binding chaperone that captures myristoylated NPHP3 via conserved hydrophobic phenylalanines in a β-sandwich fold; ARL3-GTP releases the myristoylated cargo from UNC119B; and ARL3, UNC119B, and the ARL3 GAP RP2 are all required for NPHP3 ciliary targeting. UNC119B myristoyl-binding activity is required for this function.\",\n      \"method\": \"Proteomic pulldown, directed mutagenesis of structural model, structural modeling of UNC119-myristate complex, siRNA knockdown in IMCD3 cells with ciliary localization readout, genetic requirement established by co-depletion\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural modeling with mutagenesis, biochemical interaction mapping, and functional knockdown with specific ciliary targeting readout, all in a single rigorous study\",\n      \"pmids\": [\"22085962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UNC119B functions as a lipid-binding chaperone with specificity for myristoylated proteins; UNC119B knockdown in IMCD3 cells prevents trafficking of myristoylated NPHP3 to cilia, establishing a direct role in ciliary targeting of myristoylated cargo.\",\n      \"method\": \"siRNA knockdown with ciliary localization readout; biochemical characterization of lipid-binding specificity\",\n      \"journal\": \"Vision research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review consolidating findings from multiple labs including knockdown data; functional conclusion replicated from primary study (PMID:22085962)\",\n      \"pmids\": [\"23000199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UNC119B binds myristoylated cargo peptides (GNAT1, NPHP3, Cystin1, RP2, Src) with affinities ranging from subnanomolar to micromolar; ciliary proteins bind with high affinity and are exclusively released by ARL3·GppNHp, whereas low-affinity cargo can be released by both ARL2·GppNHp and ARL3·GppNHp. X-ray structure of myristoylated NPHP3 peptide in complex with UNC119a revealed that residues at +2 and +3 positions relative to the myristoylated glycine determine binding affinity; swapping these residues between high- and low-affinity peptides reversed their affinities and partially mislocalized NPHP3.\",\n      \"method\": \"Fluorescence polarization binding assays, X-ray crystallography, site-directed mutagenesis, cellular mislocalization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structure, quantitative binding assays, and mutagenesis with functional validation in a single study\",\n      \"pmids\": [\"27481943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UNC119B (and UNC119A) binds exclusively mono-N-myristoylated peptides but does not recognize doubly lipidated or S-isoprenylated C-terminal peptides, establishing lipid specificity of the chaperone.\",\n      \"method\": \"Synthetic lipid-modified peptide binding assays to purified chaperones (biochemical specificity profiling)\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays with synthetic peptides, single lab, multiple cargo tested orthogonally\",\n      \"pmids\": [\"26503308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upregulation of UNC119B (in zebrafish unc119b and in urine-derived renal epithelial cells from human Joubert syndrome CEP290 patients) partially rescues cilia defects caused by cep290 deficiency; ectopic expression of unc119b in cep290 morphant zebrafish rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects, placing UNC119B in the lipidated protein trafficking-to-cilia pathway downstream of or in parallel with CEP290.\",\n      \"method\": \"Morpholino knockdown rescue by ectopic expression in zebrafish, human patient cell analysis, genetic epistasis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment with specific cilia phenotype readout in zebrafish model, supported by human patient cell data, single lab\",\n      \"pmids\": [\"34155518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UNC119B interacts with Rac1 and inhibits its insulin-stimulated activation, resulting in reduced GLUT4 translocation. The prenylated C-terminus of Rac1 and the small molecule C59 compete for the same binding site within UNC119B. Genetic knockdown or inhibition of UNC119B improves insulin sensitivity in rodent models of insulin resistance.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding competition assay, genetic knockdown/overexpression in cell lines, rodent models of insulin resistance with GLUT4 translocation and glucose homeostasis readouts\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction data, in vitro competition assay, and in vivo genetic manipulation with defined metabolic readout, single lab\",\n      \"pmids\": [\"40754229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UNC119B is a protein interactor of PSKH1 kinase and activates PSKH1 catalytic activity via direct engagement of the kinase domain, identified as an allosteric activator.\",\n      \"method\": \"Biochemistry and mass spectrometry-based interactome analysis, kinase activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interactor identification with kinase activity assay, single study, single lab; preprint and peer-reviewed versions concordant\",\n      \"pmids\": [\"39964718\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC119B is a myristoyl-binding chaperone that captures N-myristoylated cargo proteins (e.g., NPHP3, GNAT1, Cystin1) via a hydrophobic β-sandwich pocket with affinity determined by residues at the +2/+3 positions relative to the myristoylated glycine; ciliary delivery is completed when ARL3-GTP (but not ARL2-GTP for high-affinity cargo) displaces the cargo inside the cilium in a GTPase cycle involving the ARL3 GAP RP2, and UNC119B also inhibits Rac1 activation to suppress GLUT4 translocation and acts as an allosteric activator of PSKH1 kinase.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UNC119B is a myristoyl-binding chaperone that solubilizes and traffics N-myristoylated cargo proteins to the cilium [#0]. It captures monomyristoylated cargo such as NPHP3, GNAT1, and Cystin1 within a hydrophobic \\u03b2-sandwich pocket lined by conserved phenylalanines, binding only mono-N-myristoylated peptides and not doubly lipidated or isoprenylated termini [#0, #3]. Binding affinity ranges from subnanomolar to micromolar and is set by the residues at the +2 and +3 positions relative to the myristoylated glycine; swapping these residues reverses affinity and mislocalizes cargo [#2]. Cargo release is governed by an ARL GTPase switch: high-affinity ciliary cargo is displaced specifically by ARL3-GTP, whereas low-affinity cargo can also be released by ARL2-GTP, and efficient ciliary targeting of NPHP3 requires both ARL3 and its GAP RP2 [#0, #2]. Consistent with a role in ciliary lipidated-protein trafficking, UNC119B expression partially rescues cilia defects caused by CEP290 deficiency in zebrafish and human patient cells [#4]. Beyond cilia, UNC119B engages the prenylated C-terminus of Rac1 to inhibit insulin-stimulated Rac1 activation and GLUT4 translocation, with its loss improving insulin sensitivity in rodent models [#5], and it acts as an allosteric activator of PSKH1 kinase through direct engagement of the kinase domain [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that UNC119B, distinct from UNC119A, is a myristoyl-binding chaperone required for ciliary delivery of myristoylated cargo, answering how lipidated cargo such as NPHP3 reaches the cilium.\",\n      \"evidence\": \"Proteomic pulldown, structural modeling with mutagenesis of \\u03b2-sandwich phenylalanines, and siRNA knockdown in IMCD3 cells with ciliary localization and ARL3-GTP release readouts\",\n      \"pmids\": [\"22085962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo repertoire beyond NPHP3 not defined\", \"Atomic structure of UNC119B-myristate complex not determined in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Consolidated UNC119B as a lipid-binding chaperone with myristoyl specificity whose depletion blocks NPHP3 ciliary trafficking, reinforcing its direct trafficking role.\",\n      \"evidence\": \"siRNA knockdown with ciliary localization readout and biochemical lipid-binding characterization (review consolidation)\",\n      \"pmids\": [\"23000199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely confirmatory of prior primary work\", \"No new mechanistic detail on release step\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the lipid-recognition rule, showing the chaperone reads mono-N-myristoylation exclusively and rejects double-lipidated or isoprenylated termini.\",\n      \"evidence\": \"Binding assays of synthetic lipid-modified peptides to purified chaperone\",\n      \"pmids\": [\"26503308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro peptide assays only; cellular consequence of discrimination not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how cargo affinity is encoded and how the ARL GTPase switch sorts cargo, explaining selective ARL3-GTP-dependent release of high-affinity ciliary cargo.\",\n      \"evidence\": \"Fluorescence polarization affinity measurements, X-ray crystallography of myristoylated NPHP3 peptide complex, and +2/+3 residue swap mutagenesis with cellular mislocalization assay\",\n      \"pmids\": [\"27481943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure solved with UNC119a paralog rather than UNC119B\", \"In vivo affinity thresholds for additional cargo not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed UNC119B within the CEP290-dependent ciliary trafficking pathway by showing it can compensate for CEP290 loss.\",\n      \"evidence\": \"Morpholino knockdown rescue by ectopic unc119b expression in zebrafish and analysis of human Joubert syndrome CEP290 patient cells\",\n      \"pmids\": [\"34155518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epistatic order relative to CEP290 not fully resolved\", \"Rescue only partial for photoreceptor defects\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended UNC119B function beyond cilia, identifying it as a negative regulator of Rac1-driven GLUT4 translocation and insulin signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro binding competition with the prenylated Rac1 C-terminus and compound C59, and genetic knockdown/overexpression in cells and rodent insulin-resistance models\",\n      \"pmids\": [\"40754229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How prenyl-cargo binding reconciles with myristoyl specificity not explained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a kinase-regulatory role, with UNC119B acting as an allosteric activator of PSKH1.\",\n      \"evidence\": \"Mass spectrometry interactome analysis and kinase activity assays with direct kinase-domain engagement\",\n      \"pmids\": [\"39964718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of allosteric activation unknown\", \"Physiological context of UNC119B-PSKH1 signaling undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UNC119B reconciles myristoyl-specific cargo capture with binding to a prenylated Rac1 terminus, and how its ciliary, metabolic, and kinase-regulatory functions are coordinated in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model spanning myristoyl and prenyl cargo\", \"Tissue- and pathway-specific partitioning of functions not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NPHP3\", \"GNAT1\", \"Cystin1\", \"RP2\", \"ARL3\", \"RAC1\", \"PSKH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}