{"gene":"UNC119","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1995,"finding":"unc-119 is expressed throughout the C. elegans nervous system (unc-119/lacZ fusion reporter in neurons) and is required for locomotion, feeding, and chemosensation; loss-of-function alleles demonstrate a neural origin of the phenotype.","method":"Transgenic reporter gene (unc-119/lacZ fusion), phenotypic rescue with genomic DNA clones, characterization of multiple null alleles","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic rescue and reporter localization in single organism, multiple alleles characterized by one lab","pmids":["8582641"],"is_preprint":false},{"year":2001,"finding":"UNC-119 acts cell-autonomously in neurons to suppress axon branching and stabilize differentiated axon architecture in adult C. elegans; post-developmental expression can rescue supernumerary branching, demonstrating a maintenance rather than developmental role.","method":"Live imaging, cell-autonomous rescue experiments with tissue-specific promoters, loss-of-function analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic rescue experiments and live imaging in single lab","pmids":["11641230"],"is_preprint":false},{"year":1998,"finding":"HRG4 (UNC119) protein is localized to the cytoplasm and presynaptic membranes of photoreceptor ribbon synapses (outer plexiform layer) in human and rat retinas, consistent with a function in photoreceptor neurotransmission.","method":"Immunofluorescence microscopy (light and electron microscopic levels), Western blot analysis","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunofluorescence/EM in two species, single lab, no functional manipulation","pmids":["9538874"],"is_preprint":false},{"year":2000,"finding":"The conserved C-terminal domain of human HRG4/UNC119 (and Drosophila DmUNC-119) is functionally necessary and sufficient to rescue C. elegans unc-119 mutants, while the divergent N-terminus is dispensable; function is conserved across metazoans.","method":"Transgenic rescue in C. elegans with domain-truncated human/Drosophila UNC119 constructs under the unc-119 promoter","journal":"Journal of neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species rescue with deletion constructs defines functional domain, single lab","pmids":["10858820"],"is_preprint":false},{"year":2000,"finding":"A heterozygous premature-termination mutation in HRG4 (UNC119) causes cone-rod dystrophy; transgenic mice expressing the same truncated protein develop age-dependent retinal degeneration with defects in photoreceptor synaptic transmission (depressed b-wave, normal c-wave).","method":"Patient mutation screening, transgenic mouse model with ERG and histopathology","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient mutation confirmed in transgenic model with electrophysiological readout, single lab","pmids":["11006213"],"is_preprint":false},{"year":2002,"finding":"UNC119 associates with IL-5Rα and Src family tyrosine kinases (Lyn) and induces their catalytic activity through interaction with SH2 and SH3 domains; eosinophils transduced with UNC119 show increased Lyn activity and prolonged survival in the absence of IL-5.","method":"Yeast two-hybrid screening, co-immunoprecipitation, kinase activity assays, retroviral transduction with gain/loss-of-function","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional kinase assay, single lab","pmids":["12496276"],"is_preprint":false},{"year":2003,"finding":"HRG4 (UNC119) interacts with ARL2 via a conserved domain homologous to the ARL2-binding region of PDE-delta; interaction confirmed by yeast two-hybrid, co-immunoprecipitation, and direct binding assay; ARL2 colocalizes with HRG4 in the retina.","method":"Yeast two-hybrid, co-immunoprecipitation, direct binding assay, immunofluorescence colocalization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays (Y2H, CoIP, direct binding) in single lab","pmids":["12527357"],"is_preprint":false},{"year":2004,"finding":"UNC119 associates with CD3 and CD4, activates Lck and Fyn in T cells, and is required for IL-2 production and T cell proliferation; UNC119-deficient T cells show dramatically reduced Lck/Fyn kinase activity, rescued by UNC119 reconstitution.","method":"Co-immunoprecipitation, kinase activity assays, genetic reconstitution, loss-of-function T cell analysis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal CoIP plus kinase assay plus reconstitution, single lab","pmids":["14757743"],"is_preprint":false},{"year":2006,"finding":"Truncated mutant HRG4 (UNC119) binds ARL2 with ~3-fold higher affinity than wild-type, causing sequestration of ARL2, reduction of ANT-1 in photoreceptor synaptic mitochondria, mitochondrial dysfunction, cytochrome c release, and caspase-3 activation in synapses leading to apoptosis and trans-synaptic degeneration.","method":"Saturation binding assay, Western blot, immunofluorescence, TUNEL, morphometric analysis in transgenic mouse model","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — saturation binding quantifies affinity difference, multiple downstream readouts, single lab","pmids":["16565359"],"is_preprint":false},{"year":2006,"finding":"Knockout of HRG4 (UNC119/MRG4) in mice causes slowly progressive retinal degeneration with dysfunction primarily in the distal photoreceptor (inner/outer segment region), distinct from the synaptic degeneration seen in truncation-mutant transgenic mice, indicating dual functionality at both synaptic and distal compartments.","method":"Gene targeting (knockout mouse), ERG, histopathology (LM and EM), TUNEL, Western blot, immunofluorescence","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple phenotypic readouts compared to transgenic model, single lab","pmids":["17174953"],"is_preprint":false},{"year":2007,"finding":"UNC119 activates Fyn kinase and associates with it (co-precipitation and colocalization); UNC119 overexpression stimulates p38 (but not JNK) phosphorylation and induces α-SMA expression/myofibroblast differentiation in a Fyn- and p38 MAPK-dependent manner; UNC119 stimulates TGF-β and IL-6 production.","method":"Co-immunoprecipitation, kinase activity assay, siRNA knockdown, overexpression, SYF (Src/Yes/Fyn-null) cell rescue, p38 inhibitor experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus kinase assay plus genetic epistasis with SYF cells, single lab","pmids":["17579091"],"is_preprint":false},{"year":2008,"finding":"Munc119 (UNC119) is recruited to photoreceptor synaptic ribbons by direct interaction with the NADH-binding region of the RIBEYE(B) domain, requiring the PrBP/delta homology domain of Munc119; this interaction does not compete with NADH binding to RIBEYE.","method":"Five independent approaches: yeast two-hybrid, co-immunoprecipitation, affinity chromatography, direct binding assay, point mutagenesis of RIBEYE(B)E844Q","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — five orthogonal binding methods plus mutagenesis identifying binding-deficient mutant, single lab","pmids":["18664567"],"is_preprint":false},{"year":2008,"finding":"CaBP4 directly interacts with UNC119 at photoreceptor synapses; CaBP4-knockout mice show reduced UNC119 levels at photoreceptor terminals, suggesting CaBP4 stabilizes UNC119 there.","method":"Affinity chromatography, yeast two-hybrid, co-immunoprecipitation, gel overlay assay, immunohistochemistry, Western blot of CaBP4-KO retinas","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — four orthogonal binding methods plus KO mouse validation, single lab","pmids":["18296658"],"is_preprint":false},{"year":2009,"finding":"UNC119 directly interacts with dynamin, inhibits dynamin's GTPase activity, and decreases dynamin's association with amphiphysin; depletion of UNC119 increases, whereas overexpression inhibits, clathrin- and caveolae-based endocytosis and macropinocytosis (but not clathrin/dynamin-independent cholera toxin B uptake).","method":"Co-immunoprecipitation, GTPase activity assay, siRNA knockdown, overexpression, uptake assays with multiple cargo (transferrin, FM4-64, albumin, viruses, beads)","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus enzymatic assay plus multiple cargo uptake assays, single lab","pmids":["19781630"],"is_preprint":false},{"year":2009,"finding":"UNC119 interacts with Abl family kinases and inhibits their kinase activity, thereby inhibiting Crk phosphorylation and reducing Shigella entry into cells; UNC119 knockdown in vivo enhances bacterial invasion and lethality in a pulmonary shigellosis mouse model.","method":"Co-immunoprecipitation, kinase activity assay, siRNA knockdown, cell-permeable TAT-UNC119 rescue, in vivo mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus kinase assay plus in vivo rescue, single lab","pmids":["19381274"],"is_preprint":false},{"year":2011,"finding":"UNC119 recognizes the acylated (myristoylated/lauroylated) N-terminus of transducin α (Gαt1) and C. elegans G proteins ODR-3 and GPA-13; crystal structure at 1.95 Å reveals an immunoglobulin-like β-sandwich fold forming a hydrophobic cavity; co-crystal with acylated Tα peptide at 2.0 Å shows the lipid chain buried in the hydrophobic pocket; UNC119 binds Tα-GTP and inhibits its GTPase activity; UNC119 deletion in mouse and C. elegans causes G protein mislocalization.","method":"X-ray crystallography (1.95 Å apo, 2.0 Å co-crystal), pulldown assays, isothermal titration calorimetry (ITC), GTPase activity assay, mouse and C. elegans knockouts with localization analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + ITC + GTPase assay + two model organism knockouts, multiple orthogonal methods","pmids":["21642972"],"is_preprint":false},{"year":2011,"finding":"Human UNC119 (HRG4) binds myristoylated Gαt1 with high affinity (dependent on N-acylation, not on GTP state), can bind Gαt1-GDP and heterotrimeric transducin (Gt), displaces Gβ1γ1 from the heterotrimer, facilitates solubilization of Gt from dark-adapted rod OS membranes, and inhibits rhodopsin-dependent activation of Gt but has no effect on Gαt1 GTPase activity.","method":"Pulldown assays, ITC/binding assays, in vitro GTPase assay, membrane solubilization assay, functional G protein activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple in vitro biochemical assays with purified proteins establishing mechanistic details, single lab","pmids":["21712387"],"is_preprint":false},{"year":2011,"finding":"UNC119b (but not UNC119a) is required for ciliary targeting of the myristoylated protein NPHP3; UNC119 binding to NPHP3 requires myristoylation and maps to the N-terminal 200 residues; conserved hydrophobic β-sandwich phenylalanines are essential for myristate binding; ARL3-GTP releases myristoylated cargo from UNC119; ARL3, UNC119b, and the ARL3 GAP RP2 constitute a GTPase cycle for ciliary delivery.","method":"Proteomic approach (binding partner identification), directed mutagenesis, structural modeling, cell-based ciliary targeting assays, siRNA knockdown, C. elegans genetics","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis validated by structural model, multiple orthogonal functional assays, two model systems","pmids":["22085962"],"is_preprint":false},{"year":2012,"finding":"Both Arl2 and Arl3 bind UNC119 with similar affinity, but only Arl3-GTP allosterically displaces myristoylated cargo by accelerating its release by three orders of magnitude; crystal structures of Arl3 and Arl2 in complex with UNC119a reveal that the N-terminal amphipathic helix of Arl3·GppNHp remains surface-bound (not displaced), inducing widening of the myristoyl-binding pocket—the structural basis for Arl3 specificity.","method":"X-ray crystallography (Arl3-UNC119a and Arl2-UNC119a co-crystal structures), kinetic cargo release assays, affinity measurements","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structures plus quantitative kinetic assays define molecular mechanism, single rigorous study","pmids":["22960633"],"is_preprint":false},{"year":2014,"finding":"Poly-GA (C9orf72 DPR protein) co-aggregates with UNC119 in neurons; poly-GA expression strongly reduces soluble UNC119 levels; UNC119 knockdown alone inhibits dendritic branching and causes neurotoxicity similar to poly-GA; UNC119 overexpression partially rescues poly-GA toxicity, indicating loss-of-function as a contributing mechanism.","method":"Quantitative mass spectrometry, co-aggregation assays, siRNA knockdown, overexpression rescue in primary neurons, patient brain immunostaining","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS plus functional knockdown/rescue in neurons, single lab","pmids":["25120191"],"is_preprint":false},{"year":2014,"finding":"Genetic epistasis: knockout of Unc119 partially rescues the GRK1 transport defect in Pde6d-knockout cone photoreceptors and restores photopic ERG b-wave amplitudes, indicating that cone transport of isoprenylated (GRK1) and acylated proteins are functionally interdependent.","method":"Double knockout mouse (Pde6d; Unc119), ERG, immunolocalization","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean double-knockout genetic epistasis with functional ERG readout, single lab","pmids":["24664735"],"is_preprint":false},{"year":2016,"finding":"High-affinity myristoylated cargo peptides from ciliary proteins (GNAT1, NPHP3, Cystin1) bind Unc119a/b with subnanomolar to low-nanomolar affinity; non-ciliary Src peptide has low (micromolar) affinity; high-affinity cargo is released exclusively by Arl3·GppNHp, while low-affinity cargo is released by both Arl2 and Arl3; X-ray structure of myristoylated NPHP3 peptide in complex with Unc119a defines the +2/+3 residue positions as determinants of binding affinity; swapping +2/+3 residues reverses affinities and partially mislocalizes NPHP3.","method":"ITC/fluorescence polarization binding assays, X-ray crystallography, site-directed mutagenesis, cell-based localization assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus quantitative binding assays plus mutagenesis with cellular validation, single rigorous study","pmids":["27481943"],"is_preprint":false},{"year":2017,"finding":"UNC119 sequesters myristoylated Src family kinases (SFKs) from the cytoplasm; localized Arl2/3 activity on the recycling endosome releases SFKs from UNC119; Src is then trapped on the recycling endosome electrostatically while Fyn is trapped on the Golgi by palmitoyl acyl-transferase; vesicular trafficking restores SFK enrichment at the plasma membrane; UNC119 knockdown disrupts SFK localization and signaling activity.","method":"Live-cell imaging, FRAP, siRNA knockdown, colocalization, quantitative imaging of SFK distribution","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple live imaging and knockdown approaches, single lab, mechanistic spatial cycle defined","pmids":["28740133"],"is_preprint":false},{"year":2017,"finding":"Squarunkin A, a small molecule inhibitor, selectively inhibits binding of myristoylated Src N-terminal peptide to UNC119A with IC50 of 10 nM; it binds UNC119 proteins in cell lysate and interferes with Src kinase activation, demonstrating the UNC119–cargo interaction is druggable.","method":"Competitive binding assay (IC50 determination), cell lysate engagement, Src kinase activity assay","journal":"Angewandte Chemie (International ed. in English)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — quantitative in vitro inhibition plus cell-based kinase readout, single lab","pmids":["28471079"],"is_preprint":false},{"year":2018,"finding":"UNC119 interacts with RASSF6 and promotes the RASSF6–MDM2 interaction, stabilizing p53; UNC119 induces apoptosis via RASSF6 and p53; UNC119 depletion impairs DNA repair after DNA damage and causes polyploid cell generation.","method":"Co-immunoprecipitation, siRNA knockdown, apoptosis assays, DNA damage assays (polyploidy analysis)","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal CoIP plus functional loss-of-function assays, single lab","pmids":["29931788"],"is_preprint":false},{"year":2019,"finding":"Lipidated, hydrocarbon-stapled peptides derived from the UNC119-binding partner Gnat1 bind UNC119a and cause accumulation of cytokinetic and binucleated cells, implicating UNC119a in the completion of cytokinesis.","method":"Hydrocarbon stapling, binding assays, cell biology assays (cytokinesis/binucleation phenotype)","journal":"Chembiochem : a European journal of chemical biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological tool with phenotypic readout but indirect mechanism","pmids":["31680402"],"is_preprint":false},{"year":2020,"finding":"UNC119A interacts with the active (GTP-bound) form of KRAS; the C-terminal modification of KRAS is required for this interaction; the myristoyl-binding hydrophobic pocket of UNC119A is NOT involved; UNC119A promotes KRAS binding to RASSF6, enhancing RASSF6–MDM2 interaction and p53-dependent apoptosis; UNC119A silencing promotes soft-agar colony formation, migration, and invasiveness in KRAS-mutated cancer cells.","method":"Co-immunoprecipitation, RNAi gene silencing, immunofluorescence, cell biology assays (soft-agar colony formation, migration, invasion)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal CoIP plus domain mapping plus multiple functional assays, single lab","pmids":["32554467"],"is_preprint":false},{"year":2023,"finding":"Deletion of one or both UNC119 alleles in mice reduces steady-state glutamate release rate at rod synapses (depolarizes rod bipolar cell membrane potential, decreases sensitivity, accelerates response decay, decreases Hill coefficient), without changing rod outer segment photocurrent or synaptic Ca2+ current voltage dependence; UNC119 facilitates glutamate release at rod ribbon synapses, likely via interaction with RIBEYE or other synaptic proteins rather than CaBP4 or calcium channels.","method":"Patch-clamp recordings from retinal slices in UNC119 heterozygous and homozygous knockout mice, bright-light transducin translocation experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiological recordings in knockout mice with multiple readouts, single lab","pmids":["37175812"],"is_preprint":false},{"year":2025,"finding":"UNC119 interacts with cone-specific transducin α-subunit Gnat2 and is required for translocation of Gnat2 to the outer segment in cone photoreceptors; Unc119-deficient mice show progressive cone-rod dystrophy with activation of JAK-STAT and NF-κB inflammatory pathways; a human CRD-associated UNC119 mutant competitively inhibits the UNC119–GNAT1/GNAT2 interaction; curcumin treatment suppresses inflammation and cone degeneration in Unc119-deficient retinas.","method":"Co-immunoprecipitation, Unc119 knockout mouse, RNA-seq/bioinformatics, immunofluorescence, curcumin pharmacological rescue","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus knockout mouse with transcriptomic pathway analysis and pharmacological rescue, single lab","pmids":["41107067"],"is_preprint":false},{"year":2025,"finding":"UNC119 directly traffics LCK to the immunological synapse in T cells; inhibiting UNC119 reduces LCK localization at the synapse without impairing LCK phosphorylation, and reduces TCR signal transduction; UNC119 sustains proliferation in T-ALL cells.","method":"Immunofluorescence localization, UNC119 inhibition (pharmacological), TCR signaling assays, proliferation assays in primary T cells and patient-derived T-ALL cells","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional signaling readout plus disease-relevant cell line validation, single lab","pmids":["39814552"],"is_preprint":false}],"current_model":"UNC119 is a lipid-binding chaperone with an immunoglobulin-like β-sandwich fold that forms a hydrophobic pocket to sequester the N-terminal myristoyl (or lauroyl) chains of diverse cargo proteins—including transducin α-subunits, Src family kinases, NPHP3, Gnat2, and LCK—shielding them from membranes and enabling their cytoplasmic diffusion; Arl3-GTP (and, for low-affinity cargo, also Arl2-GTP) allosterically displaces cargo from UNC119's hydrophobic pocket at the cilium or recycling endosome to deliver myristoylated proteins to specific membrane compartments, forming an ARL3-UNC119-RP2 GTPase cycle essential for ciliary targeting; at the photoreceptor ribbon synapse, UNC119 is recruited by RIBEYE and CaBP4 and facilitates glutamate release; in immune cells, UNC119 activates Lck/Fyn/Lyn/Abl kinases by direct interaction and traffics LCK to the immunological synapse; UNC119 also inhibits dynamin GTPase activity to regulate endocytosis and interacts with RASSF6 to promote KRAS/p53-dependent apoptosis."},"narrative":{"mechanistic_narrative":"UNC119 is a lipid-binding chaperone that solubilizes N-terminally acylated proteins and delivers them to specific membrane compartments, a role conserved from C. elegans neurons to the mammalian photoreceptor and immune system [PMID:8582641, PMID:21642972]. Its immunoglobulin-like β-sandwich fold forms a hydrophobic cavity that buries the myristoyl (or lauroyl) chain of cargo such as transducin α (Gαt1/GNAT1), the cone transducin Gnat2, NPHP3, and Src-family kinases, shielding the lipid from membranes and enabling cytoplasmic diffusion; binding depends on N-acylation and on +2/+3 residue identity that tunes affinity from subnanomolar (ciliary cargo) to micromolar (Src) [PMID:21642972, PMID:21712387, PMID:27481943]. Cargo is released by an Arl3-GTP–driven allosteric switch: although both Arl2 and Arl3 bind UNC119, only Arl3·GTP retains its N-terminal amphipathic helix surface-bound and widens the myristoyl pocket to accelerate cargo release by orders of magnitude, with high-affinity cargo released exclusively by Arl3 and low-affinity cargo by either GTPase [PMID:22960633, PMID:27481943]. This release occurs at the cilium, where UNC119b together with Arl3 and the Arl3-GAP RP2 forms a GTPase cycle that targets myristoylated NPHP3, and at the recycling endosome, where Arl2/3 activity liberates Src-family kinases for vesicular delivery to the plasma membrane [PMID:22085962, PMID:28740133]. In photoreceptors UNC119 governs light-driven transducin solubilization and translocation of Gαt1 and Gnat2 to the outer segment, and is independently recruited to the ribbon synapse by direct interaction with the RIBEYE(B) domain and stabilized by CaBP4, where it facilitates glutamate release [PMID:21712387, PMID:18664567, PMID:18296658, PMID:37175812, PMID:41107067]. In immune cells UNC119 binds and activates Lck, Fyn, Lyn, and Abl kinases and traffics LCK to the immunological synapse to sustain TCR signaling and T cell proliferation [PMID:12496276, PMID:14757743, PMID:39814552]. Beyond cargo chaperoning, UNC119 directly inhibits dynamin GTPase activity to restrain endocytosis [PMID:19781630], and interacts with active KRAS and RASSF6 to stabilize p53 and promote apoptosis through a pocket-independent surface [PMID:29931788, PMID:32554467]. Premature-termination mutations in UNC119 cause cone-rod dystrophy, and Unc119-deficient mice develop progressive retinal degeneration with JAK-STAT and NF-κB inflammatory activation [PMID:11006213, PMID:41107067].","teleology":[{"year":1995,"claim":"Established that unc-119 is a nervous-system gene required for behavior, anchoring its biology to neurons before any molecular function was known.","evidence":"unc-119/lacZ reporter, genomic rescue, and null-allele phenotyping in C. elegans","pmids":["8582641"],"confidence":"Medium","gaps":["No molecular activity defined","Cell type of action within the nervous system not resolved at this stage"]},{"year":1998,"claim":"Localized the mammalian ortholog (HRG4) to photoreceptor ribbon synapses, the first link to retinal neurotransmission.","evidence":"Immunofluorescence and EM localization plus Western blot in human and rat retina","pmids":["9538874"],"confidence":"Medium","gaps":["No functional manipulation","Synaptic mechanism not defined"]},{"year":2000,"claim":"Defined the conserved C-terminal domain as the functional unit and tied a human truncation mutation to cone-rod dystrophy with a synaptic transmission defect, providing the first disease connection.","evidence":"Cross-species domain-truncation rescue in C. elegans; patient mutation screen with transgenic mouse ERG/histopathology","pmids":["10858820","11006213"],"confidence":"Medium","gaps":["Biochemical basis of the domain function unknown","Dominant mechanism of the truncation not yet explained"]},{"year":2003,"claim":"Identified ARL2 as a direct binding partner via a PDE-delta-homologous domain, first connecting UNC119 to an Arf-like GTPase.","evidence":"Yeast two-hybrid, co-IP, direct binding, and retinal colocalization","pmids":["12527357"],"confidence":"Medium","gaps":["Functional consequence of ARL2 binding undefined","Arl2 vs Arl3 specificity not addressed"]},{"year":2004,"claim":"Revealed an immune function: UNC119 activates Src-family kinases (Lck/Fyn) downstream of CD3/CD4 to drive T cell IL-2 production and proliferation, extending its role beyond the retina.","evidence":"Reciprocal co-IP, kinase assays, and genetic reconstitution in UNC119-deficient T cells (building on IL-5Rα/Lyn work in eosinophils)","pmids":["14757743","12496276"],"confidence":"Medium","gaps":["Mechanism of kinase activation unclear","Relationship to lipid-binding pocket not yet known"]},{"year":2006,"claim":"Explained dominant retinal disease by showing the truncated mutant binds ARL2 with higher affinity, sequestering it and triggering mitochondrial-dependent synaptic apoptosis, while knockout revealed a separate distal photoreceptor role.","evidence":"Saturation binding affinity, TUNEL/morphometry in transgenic mice, and gene-targeted knockout with ERG/histology","pmids":["16565359","17174953"],"confidence":"Medium","gaps":["Molecular cargo at distal vs synaptic compartments not identified","Direct vs indirect role in apoptosis unresolved"]},{"year":2008,"claim":"Defined how UNC119 is targeted to the ribbon synapse, through direct PrBP/delta-domain binding to RIBEYE(B) and stabilization by CaBP4.","evidence":"Five orthogonal binding methods with RIBEYE point mutagenesis; affinity/Y2H/co-IP plus CaBP4-KO retina analysis","pmids":["18664567","18296658"],"confidence":"High","gaps":["How synaptic recruitment relates to the cargo-chaperone activity unclear","Functional output of synaptic UNC119 not yet measured"]},{"year":2009,"claim":"Broadened the kinase/trafficking repertoire by showing UNC119 inhibits dynamin GTPase to restrain endocytosis and inhibits Abl kinases to limit bacterial invasion.","evidence":"Co-IP, GTPase and kinase assays, multi-cargo uptake assays, and an in vivo shigellosis mouse model","pmids":["19781630","19381274"],"confidence":"Medium","gaps":["Structural basis of dynamin/Abl inhibition unknown","Whether these activities share the lipid pocket undefined"]},{"year":2011,"claim":"Resolved the core molecular mechanism: UNC119 is a myristoyl-binding chaperone with an Ig-like β-sandwich pocket that sequesters acylated transducin α and is required for G protein localization.","evidence":"Apo and co-crystal X-ray structures, ITC, GTPase assays, and mouse/C. elegans knockouts; parallel human biochemistry showing acyl-dependent Gαt binding and transducin solubilization","pmids":["21642972","21712387"],"confidence":"High","gaps":["Cargo-release trigger not yet defined","Conflicting effects on Gαt GTPase between studies"]},{"year":2011,"claim":"Placed UNC119 in a ciliary delivery cycle by showing UNC119b carries myristoylated NPHP3 and that Arl3-GTP releases cargo within an ARL3–UNC119b–RP2 GTPase module.","evidence":"Proteomics, mutagenesis with structural modeling, ciliary targeting assays, and C. elegans genetics","pmids":["22085962"],"confidence":"High","gaps":["Why only UNC119b functions in ciliary NPHP3 targeting unexplained at structural level","Isoform-specific cargo repertoire incomplete"]},{"year":2012,"claim":"Defined the structural basis of Arl3 specificity: only Arl3-GTP keeps its amphipathic helix surface-bound and widens the myristoyl pocket to accelerate cargo release ~1000-fold, distinguishing it from Arl2.","evidence":"Co-crystal structures of Arl3- and Arl2-UNC119a with kinetic release and affinity assays","pmids":["22960633"],"confidence":"High","gaps":["In vivo compartment where each GTPase acts not yet mapped"]},{"year":2016,"claim":"Established a cargo affinity code: +2/+3 residues set subnanomolar (ciliary) versus micromolar (Src) affinity, dictating whether cargo is released only by Arl3 or by both Arl2 and Arl3.","evidence":"ITC/FP binding, NPHP3-peptide co-crystal, and residue-swap mutagenesis with cellular localization","pmids":["27481943"],"confidence":"High","gaps":["Full cargo set across tissues not enumerated","How affinity maps to compartment specificity in vivo only partly tested"]},{"year":2014,"claim":"Linked UNC119-dependent acyl-cargo transport to prenyl-cargo transport, showing Unc119 loss partially rescues the GRK1 defect of Pde6d-knockout cones.","evidence":"Pde6d;Unc119 double-knockout mice with ERG and immunolocalization","pmids":["24664735"],"confidence":"Medium","gaps":["Molecular basis of the UNC119/PDE6D crosstalk unresolved"]},{"year":2017,"claim":"Showed how the chaperone integrates with membrane trafficking: localized Arl2/3 activity on recycling endosomes releases Src-family kinases from UNC119 for compartment-specific re-targeting, and that the cargo interaction is druggable.","evidence":"Live imaging/FRAP/knockdown of SFK distribution; competitive small-molecule inhibitor (Squarunkin A, 10 nM) with cell-based kinase readout","pmids":["28740133","28471079"],"confidence":"Medium","gaps":["Endogenous spatial regulators of Arl activity not identified","Therapeutic relevance of inhibition untested in disease models"]},{"year":2018,"claim":"Uncovered a non-canonical tumor-suppressive role through RASSF6-MDM2-p53 signaling and a DNA-damage/ploidy phenotype, separate from cargo chaperoning.","evidence":"Reciprocal co-IP, knockdown, apoptosis and polyploidy assays","pmids":["29931788"],"confidence":"Medium","gaps":["Direct vs indirect role in DNA repair unclear","Connection to the lipid pocket not addressed here"]},{"year":2020,"claim":"Showed UNC119A engages active KRAS through a pocket-independent surface and bridges KRAS-RASSF6-MDM2 to promote p53-dependent apoptosis, defining a tumor-suppressive axis in KRAS-mutant cancer.","evidence":"Co-IP with domain mapping, RNAi silencing, and soft-agar/migration/invasion assays","pmids":["32554467"],"confidence":"Medium","gaps":["Structural basis of KRAS binding unknown","Whether this competes with lipid-cargo function in cells untested"]},{"year":2023,"claim":"Provided direct functional evidence that synaptic UNC119 sets the rate of glutamate release at rod ribbon synapses, independent of CaBP4 or calcium channels.","evidence":"Patch-clamp from retinal slices of Unc119 heterozygous and homozygous knockout mice","pmids":["37175812"],"confidence":"Medium","gaps":["Molecular mechanism coupling UNC119 to release machinery undefined","Which synaptic partner mediates the effect unresolved"]},{"year":2025,"claim":"Extended the cargo and disease picture: UNC119 carries cone transducin Gnat2 to the outer segment, its loss drives inflammatory cone-rod dystrophy via JAK-STAT/NF-κB, and it traffics LCK to the immunological synapse to sustain T-ALL proliferation.","evidence":"Co-IP, Unc119-knockout mice with RNA-seq and curcumin rescue; immunofluorescence and TCR/proliferation assays in primary and T-ALL cells","pmids":["41107067","39814552"],"confidence":"Medium","gaps":["Mechanism linking cargo mislocalization to inflammatory signaling unclear","How LCK trafficking by UNC119 integrates with prior SFK-activation data not reconciled"]},{"year":null,"claim":"How UNC119's distinct activities — myristoyl-cargo chaperoning, kinase activation, dynamin inhibition, synaptic glutamate release, and KRAS/RASSF6/p53 signaling — are coordinated within a single protein, and whether they share or partition structural surfaces, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking pocket-dependent and pocket-independent functions","Isoform-specific (UNC119a vs UNC119b) division of labor only partly mapped","Physiological cargo set across non-retinal tissues incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[15,16,17,21]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[15,16,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,13,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[17,22]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,16,22]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[17,21]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,22]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[17,22,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,26,29]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,22]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[16,27,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,29]}],"complexes":["ARL3-UNC119b-RP2 ciliary GTPase cycle"],"partners":["ARL3","ARL2","GNAT1","GNAT2","NPHP3","RIBEYE","LCK","KRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13432","full_name":"Protein unc-119 homolog A","aliases":["Retinal protein 4","hRG4"],"length_aa":240,"mass_kda":27.0,"function":"Involved in synaptic functions in photoreceptor cells, the signal transduction in immune cells as a Src family kinase activator, endosome recycling, the uptake of bacteria and endocytosis, protein trafficking in sensory neurons and as lipid-binding chaperone with specificity for a diverse subset of myristoylated proteins. Specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated GNAT1 and is required for G-protein localization and trafficking in sensory neurons. Probably plays a role in trafficking proteins in photoreceptor cells. Plays important roles in mediating Src family kinase signals for the completion of cytokinesis via RAB11A","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q13432/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UNC119","classification":"Not Classified","n_dependent_lines":71,"n_total_lines":1208,"dependency_fraction":0.058774834437086095},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UNC119","total_profiled":1310},"omim":[{"mim_id":"620513","title":"UNC119 LIPID-BINDING CHAPERONE B; UNC119B","url":"https://www.omim.org/entry/620513"},{"mim_id":"620342","title":"CONE-ROD DYSTROPHY 24; CORD24","url":"https://www.omim.org/entry/620342"},{"mim_id":"619926","title":"KELCH-LIKE FAMILY, MEMBER 18; KLHL18","url":"https://www.omim.org/entry/619926"},{"mim_id":"615518","title":"IMMUNODEFICIENCY 13; IMD13","url":"https://www.omim.org/entry/615518"},{"mim_id":"604695","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 3; ARL3","url":"https://www.omim.org/entry/604695"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":1084.9}],"url":"https://www.proteinatlas.org/search/UNC119"},"hgnc":{"alias_symbol":["HRG4","POC7","POC7A"],"prev_symbol":[]},"alphafold":{"accession":"Q13432","domains":[{"cath_id":"2.70.50.40","chopping":"63-115_133-236","consensus_level":"high","plddt":92.8589,"start":63,"end":236}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13432","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13432-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13432-F1-predicted_aligned_error_v6.png","plddt_mean":77.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UNC119","jax_strain_url":"https://www.jax.org/strain/search?query=UNC119"},"sequence":{"accession":"Q13432","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13432.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13432/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13432"}},"corpus_meta":[{"pmid":"8582641","id":"PMC_8582641","title":"Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system.","date":"1995","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8582641","citation_count":389,"is_preprint":false},{"pmid":"25120191","id":"PMC_25120191","title":"C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration.","date":"2014","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/25120191","citation_count":261,"is_preprint":false},{"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":"21642972","id":"PMC_21642972","title":"UNC119 is required for G protein trafficking in sensory neurons.","date":"2011","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21642972","citation_count":147,"is_preprint":false},{"pmid":"11006213","id":"PMC_11006213","title":"HRG4 (UNC119) mutation found in cone-rod dystrophy causes retinal degeneration in a transgenic model.","date":"2000","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/11006213","citation_count":103,"is_preprint":false},{"pmid":"22960633","id":"PMC_22960633","title":"Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22960633","citation_count":93,"is_preprint":false},{"pmid":"14757743","id":"PMC_14757743","title":"Unc119, a novel activator of Lck/Fyn, is essential for T cell activation.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14757743","citation_count":76,"is_preprint":false},{"pmid":"8996090","id":"PMC_8996090","title":"Conservation of function and expression of unc-119 from two Caenorhabditis species despite divergence of non-coding DNA.","date":"1996","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8996090","citation_count":65,"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":"11641230","id":"PMC_11641230","title":"UNC-119 suppresses axon branching in C. elegans.","date":"2001","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11641230","citation_count":55,"is_preprint":false},{"pmid":"18664567","id":"PMC_18664567","title":"RIBEYE recruits Munc119, a mammalian ortholog of the Caenorhabditis elegans protein unc119, to synaptic ribbons of photoreceptor synapses.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18664567","citation_count":54,"is_preprint":false},{"pmid":"12496276","id":"PMC_12496276","title":"Identification of UNC119 as a novel activator of SRC-type tyrosine kinases.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12496276","citation_count":51,"is_preprint":false},{"pmid":"12527357","id":"PMC_12527357","title":"Photoreceptor synaptic protein HRG4 (UNC119) interacts with ARL2 via a putative conserved domain.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12527357","citation_count":44,"is_preprint":false},{"pmid":"9538874","id":"PMC_9538874","title":"Localization of HRG4, a photoreceptor protein homologous to Unc-119, in ribbon synapse.","date":"1998","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9538874","citation_count":44,"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":"10858820","id":"PMC_10858820","title":"The UNC-119 family of neural proteins is functionally conserved between humans, Drosophila and C. elegans.","date":"2000","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/10858820","citation_count":40,"is_preprint":false},{"pmid":"18296658","id":"PMC_18296658","title":"Interaction and colocalization of CaBP4 and Unc119 (MRG4) in photoreceptors.","date":"2008","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/18296658","citation_count":38,"is_preprint":false},{"pmid":"17174953","id":"PMC_17174953","title":"Targeted inactivation of synaptic HRG4 (UNC119) causes dysfunction in the distal photoreceptor and slow retinal degeneration, revealing a new function.","date":"2006","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/17174953","citation_count":37,"is_preprint":false},{"pmid":"21712387","id":"PMC_21712387","title":"Interaction of transducin with uncoordinated 119 protein (UNC119): implications for the model of transducin trafficking in rod photoreceptors.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21712387","citation_count":34,"is_preprint":false},{"pmid":"9761287","id":"PMC_9761287","title":"Mammalian orthologs of C. elegans unc-119 highly expressed in photoreceptors.","date":"1998","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9761287","citation_count":34,"is_preprint":false},{"pmid":"17579091","id":"PMC_17579091","title":"Unc119 regulates myofibroblast differentiation through the activation of Fyn and the p38 MAPK pathway.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17579091","citation_count":28,"is_preprint":false},{"pmid":"15593328","id":"PMC_15593328","title":"unc-119 homolog required for normal development of the zebrafish nervous system.","date":"2004","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/15593328","citation_count":26,"is_preprint":false},{"pmid":"10329014","id":"PMC_10329014","title":"Characterization of the gene for HRG4 (UNC119), a novel photoreceptor synaptic protein homologous to unc-119.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10329014","citation_count":22,"is_preprint":false},{"pmid":"28740133","id":"PMC_28740133","title":"Spatial cycles mediated by UNC119 solubilisation maintain Src family kinases plasma membrane localisation.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28740133","citation_count":21,"is_preprint":false},{"pmid":"28471079","id":"PMC_28471079","title":"Small-Molecule Inhibition of the UNC119-Cargo Interaction.","date":"2017","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/28471079","citation_count":16,"is_preprint":false},{"pmid":"11818371","id":"PMC_11818371","title":"Changes in retinal synaptic proteins in the transgenic model expressing a mutant HRG4 (UNC119).","date":"2002","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/11818371","citation_count":16,"is_preprint":false},{"pmid":"26031360","id":"PMC_26031360","title":"Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26031360","citation_count":16,"is_preprint":false},{"pmid":"19781630","id":"PMC_19781630","title":"UNC119 inhibits dynamin and dynamin-dependent endocytic processes.","date":"2009","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/19781630","citation_count":15,"is_preprint":false},{"pmid":"16565359","id":"PMC_16565359","title":"Truncation mutation in HRG4 (UNC119) leads to mitochondrial ANT-1-mediated photoreceptor synaptic and retinal degeneration by apoptosis.","date":"2006","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/16565359","citation_count":13,"is_preprint":false},{"pmid":"19381274","id":"PMC_19381274","title":"Unc119 protects from Shigella infection by inhibiting the Abl family kinases.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19381274","citation_count":12,"is_preprint":false},{"pmid":"22729960","id":"PMC_22729960","title":"Consequences of a mutation in the UNC119 gene for T cell function in idiopathic CD4 lymphopenia.","date":"2012","source":"Current allergy and asthma reports","url":"https://pubmed.ncbi.nlm.nih.gov/22729960","citation_count":11,"is_preprint":false},{"pmid":"31679307","id":"PMC_31679307","title":"Curcumin Modulates Hepatocellular Carcinoma by Reducing UNC119 Expression.","date":"2019","source":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31679307","citation_count":10,"is_preprint":false},{"pmid":"17123749","id":"PMC_17123749","title":"NgUNC-119, Naegleria homologue of UNC-119, localizes to the flagellar rootlet.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17123749","citation_count":10,"is_preprint":false},{"pmid":"31680402","id":"PMC_31680402","title":"Lipidated Stapled Peptides Targeting the Acyl Binding Protein UNC119.","date":"2019","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31680402","citation_count":8,"is_preprint":false},{"pmid":"30129686","id":"PMC_30129686","title":"Photoactivatable Myristic Acid Probes for UNC119-Cargo Interactions.","date":"2018","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30129686","citation_count":7,"is_preprint":false},{"pmid":"27669172","id":"PMC_27669172","title":"UNC119 mediates gambogic acid-induced cell-cycle dysregulation through the Gsk3β/β-catenin pathway in hepatocellular carcinoma cells.","date":"2016","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/27669172","citation_count":5,"is_preprint":false},{"pmid":"30610799","id":"PMC_30610799","title":"UNC119 promoted cell growth and migration by Wnt/β-catenin signal and TGF-β/EMT signal pathway in hepatocellular carcinoma.","date":"2018","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30610799","citation_count":5,"is_preprint":false},{"pmid":"38872845","id":"PMC_38872845","title":"Streamlined single shot safe harbor transgene integration in C. elegans using unc-119 rescue.","date":"2024","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/38872845","citation_count":5,"is_preprint":false},{"pmid":"15892079","id":"PMC_15892079","title":"Novel Caenorhabditis elegans unc-119 axon outgrowth defects correlate with behavioral phenotypes that are partially rescued by nonneural unc-119.","date":"2005","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/15892079","citation_count":5,"is_preprint":false},{"pmid":"24664735","id":"PMC_24664735","title":"Unc119 gene deletion partially rescues the GRK1 transport defect of Pde6d (- /-) cones.","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/24664735","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":"32554467","id":"PMC_32554467","title":"The RAS-interacting chaperone UNC119 drives the RASSF6-MDM2-p53 axis and antagonizes RAS-mediated malignant transformation.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32554467","citation_count":4,"is_preprint":false},{"pmid":"29552781","id":"PMC_29552781","title":"UNC119 promotes the growth and migration of hepatocellular carcinoma via Wnt/β-catenin and TGF-β/EMT signaling pathways.","date":"2018","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29552781","citation_count":3,"is_preprint":false},{"pmid":"37175812","id":"PMC_37175812","title":"A Novel Role for UNC119 as an Enhancer of Synaptic Transmission.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37175812","citation_count":2,"is_preprint":false},{"pmid":"39814552","id":"PMC_39814552","title":"UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.","date":"2025","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39814552","citation_count":1,"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":"41107067","id":"PMC_41107067","title":"Dysfunction of Unc119, a Transducin-Binding Protein, Leads to Cone-Rod Dystrophy through Activating JAK-Stat and NF-κB Inflammatory Pathways in the Mouse Retina.","date":"2025","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41107067","citation_count":0,"is_preprint":false},{"pmid":"29552782","id":"PMC_29552782","title":"UNC119 promotes the growth and migration of hepatocellular carcinoma via Wnt/β/catenin and TGF/β-EMT signaling pathways.","date":"2018","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29552782","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24108,"output_tokens":7353,"usd":0.09131,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16700,"output_tokens":5854,"usd":0.114925,"stage2_stop_reason":"end_turn"},"total_usd":0.206235,"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\": 1995,\n      \"finding\": \"unc-119 is expressed throughout the C. elegans nervous system (unc-119/lacZ fusion reporter in neurons) and is required for locomotion, feeding, and chemosensation; loss-of-function alleles demonstrate a neural origin of the phenotype.\",\n      \"method\": \"Transgenic reporter gene (unc-119/lacZ fusion), phenotypic rescue with genomic DNA clones, characterization of multiple null alleles\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic rescue and reporter localization in single organism, multiple alleles characterized by one lab\",\n      \"pmids\": [\"8582641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UNC-119 acts cell-autonomously in neurons to suppress axon branching and stabilize differentiated axon architecture in adult C. elegans; post-developmental expression can rescue supernumerary branching, demonstrating a maintenance rather than developmental role.\",\n      \"method\": \"Live imaging, cell-autonomous rescue experiments with tissue-specific promoters, loss-of-function analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic rescue experiments and live imaging in single lab\",\n      \"pmids\": [\"11641230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HRG4 (UNC119) protein is localized to the cytoplasm and presynaptic membranes of photoreceptor ribbon synapses (outer plexiform layer) in human and rat retinas, consistent with a function in photoreceptor neurotransmission.\",\n      \"method\": \"Immunofluorescence microscopy (light and electron microscopic levels), Western blot analysis\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunofluorescence/EM in two species, single lab, no functional manipulation\",\n      \"pmids\": [\"9538874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The conserved C-terminal domain of human HRG4/UNC119 (and Drosophila DmUNC-119) is functionally necessary and sufficient to rescue C. elegans unc-119 mutants, while the divergent N-terminus is dispensable; function is conserved across metazoans.\",\n      \"method\": \"Transgenic rescue in C. elegans with domain-truncated human/Drosophila UNC119 constructs under the unc-119 promoter\",\n      \"journal\": \"Journal of neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species rescue with deletion constructs defines functional domain, single lab\",\n      \"pmids\": [\"10858820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A heterozygous premature-termination mutation in HRG4 (UNC119) causes cone-rod dystrophy; transgenic mice expressing the same truncated protein develop age-dependent retinal degeneration with defects in photoreceptor synaptic transmission (depressed b-wave, normal c-wave).\",\n      \"method\": \"Patient mutation screening, transgenic mouse model with ERG and histopathology\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient mutation confirmed in transgenic model with electrophysiological readout, single lab\",\n      \"pmids\": [\"11006213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"UNC119 associates with IL-5Rα and Src family tyrosine kinases (Lyn) and induces their catalytic activity through interaction with SH2 and SH3 domains; eosinophils transduced with UNC119 show increased Lyn activity and prolonged survival in the absence of IL-5.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, kinase activity assays, retroviral transduction with gain/loss-of-function\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional kinase assay, single lab\",\n      \"pmids\": [\"12496276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HRG4 (UNC119) interacts with ARL2 via a conserved domain homologous to the ARL2-binding region of PDE-delta; interaction confirmed by yeast two-hybrid, co-immunoprecipitation, and direct binding assay; ARL2 colocalizes with HRG4 in the retina.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, direct binding assay, immunofluorescence colocalization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays (Y2H, CoIP, direct binding) in single lab\",\n      \"pmids\": [\"12527357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"UNC119 associates with CD3 and CD4, activates Lck and Fyn in T cells, and is required for IL-2 production and T cell proliferation; UNC119-deficient T cells show dramatically reduced Lck/Fyn kinase activity, rescued by UNC119 reconstitution.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, genetic reconstitution, loss-of-function T cell analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CoIP plus kinase assay plus reconstitution, single lab\",\n      \"pmids\": [\"14757743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Truncated mutant HRG4 (UNC119) binds ARL2 with ~3-fold higher affinity than wild-type, causing sequestration of ARL2, reduction of ANT-1 in photoreceptor synaptic mitochondria, mitochondrial dysfunction, cytochrome c release, and caspase-3 activation in synapses leading to apoptosis and trans-synaptic degeneration.\",\n      \"method\": \"Saturation binding assay, Western blot, immunofluorescence, TUNEL, morphometric analysis in transgenic mouse model\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — saturation binding quantifies affinity difference, multiple downstream readouts, single lab\",\n      \"pmids\": [\"16565359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Knockout of HRG4 (UNC119/MRG4) in mice causes slowly progressive retinal degeneration with dysfunction primarily in the distal photoreceptor (inner/outer segment region), distinct from the synaptic degeneration seen in truncation-mutant transgenic mice, indicating dual functionality at both synaptic and distal compartments.\",\n      \"method\": \"Gene targeting (knockout mouse), ERG, histopathology (LM and EM), TUNEL, Western blot, immunofluorescence\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple phenotypic readouts compared to transgenic model, single lab\",\n      \"pmids\": [\"17174953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC119 activates Fyn kinase and associates with it (co-precipitation and colocalization); UNC119 overexpression stimulates p38 (but not JNK) phosphorylation and induces α-SMA expression/myofibroblast differentiation in a Fyn- and p38 MAPK-dependent manner; UNC119 stimulates TGF-β and IL-6 production.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, siRNA knockdown, overexpression, SYF (Src/Yes/Fyn-null) cell rescue, p38 inhibitor experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus kinase assay plus genetic epistasis with SYF cells, single lab\",\n      \"pmids\": [\"17579091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Munc119 (UNC119) is recruited to photoreceptor synaptic ribbons by direct interaction with the NADH-binding region of the RIBEYE(B) domain, requiring the PrBP/delta homology domain of Munc119; this interaction does not compete with NADH binding to RIBEYE.\",\n      \"method\": \"Five independent approaches: yeast two-hybrid, co-immunoprecipitation, affinity chromatography, direct binding assay, point mutagenesis of RIBEYE(B)E844Q\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — five orthogonal binding methods plus mutagenesis identifying binding-deficient mutant, single lab\",\n      \"pmids\": [\"18664567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CaBP4 directly interacts with UNC119 at photoreceptor synapses; CaBP4-knockout mice show reduced UNC119 levels at photoreceptor terminals, suggesting CaBP4 stabilizes UNC119 there.\",\n      \"method\": \"Affinity chromatography, yeast two-hybrid, co-immunoprecipitation, gel overlay assay, immunohistochemistry, Western blot of CaBP4-KO retinas\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four orthogonal binding methods plus KO mouse validation, single lab\",\n      \"pmids\": [\"18296658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC119 directly interacts with dynamin, inhibits dynamin's GTPase activity, and decreases dynamin's association with amphiphysin; depletion of UNC119 increases, whereas overexpression inhibits, clathrin- and caveolae-based endocytosis and macropinocytosis (but not clathrin/dynamin-independent cholera toxin B uptake).\",\n      \"method\": \"Co-immunoprecipitation, GTPase activity assay, siRNA knockdown, overexpression, uptake assays with multiple cargo (transferrin, FM4-64, albumin, viruses, beads)\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus enzymatic assay plus multiple cargo uptake assays, single lab\",\n      \"pmids\": [\"19781630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC119 interacts with Abl family kinases and inhibits their kinase activity, thereby inhibiting Crk phosphorylation and reducing Shigella entry into cells; UNC119 knockdown in vivo enhances bacterial invasion and lethality in a pulmonary shigellosis mouse model.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, siRNA knockdown, cell-permeable TAT-UNC119 rescue, in vivo mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus kinase assay plus in vivo rescue, single lab\",\n      \"pmids\": [\"19381274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UNC119 recognizes the acylated (myristoylated/lauroylated) N-terminus of transducin α (Gαt1) and C. elegans G proteins ODR-3 and GPA-13; crystal structure at 1.95 Å reveals an immunoglobulin-like β-sandwich fold forming a hydrophobic cavity; co-crystal with acylated Tα peptide at 2.0 Å shows the lipid chain buried in the hydrophobic pocket; UNC119 binds Tα-GTP and inhibits its GTPase activity; UNC119 deletion in mouse and C. elegans causes G protein mislocalization.\",\n      \"method\": \"X-ray crystallography (1.95 Å apo, 2.0 Å co-crystal), pulldown assays, isothermal titration calorimetry (ITC), GTPase activity assay, mouse and C. elegans knockouts with localization analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + ITC + GTPase assay + two model organism knockouts, multiple orthogonal methods\",\n      \"pmids\": [\"21642972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human UNC119 (HRG4) binds myristoylated Gαt1 with high affinity (dependent on N-acylation, not on GTP state), can bind Gαt1-GDP and heterotrimeric transducin (Gt), displaces Gβ1γ1 from the heterotrimer, facilitates solubilization of Gt from dark-adapted rod OS membranes, and inhibits rhodopsin-dependent activation of Gt but has no effect on Gαt1 GTPase activity.\",\n      \"method\": \"Pulldown assays, ITC/binding assays, in vitro GTPase assay, membrane solubilization assay, functional G protein activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple in vitro biochemical assays with purified proteins establishing mechanistic details, single lab\",\n      \"pmids\": [\"21712387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UNC119b (but not UNC119a) is required for ciliary targeting of the myristoylated protein NPHP3; UNC119 binding to NPHP3 requires myristoylation and maps to the N-terminal 200 residues; conserved hydrophobic β-sandwich phenylalanines are essential for myristate binding; ARL3-GTP releases myristoylated cargo from UNC119; ARL3, UNC119b, and the ARL3 GAP RP2 constitute a GTPase cycle for ciliary delivery.\",\n      \"method\": \"Proteomic approach (binding partner identification), directed mutagenesis, structural modeling, cell-based ciliary targeting assays, siRNA knockdown, C. elegans genetics\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis validated by structural model, multiple orthogonal functional assays, two model systems\",\n      \"pmids\": [\"22085962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Both Arl2 and Arl3 bind UNC119 with similar affinity, but only Arl3-GTP allosterically displaces myristoylated cargo by accelerating its release by three orders of magnitude; crystal structures of Arl3 and Arl2 in complex with UNC119a reveal that the N-terminal amphipathic helix of Arl3·GppNHp remains surface-bound (not displaced), inducing widening of the myristoyl-binding pocket—the structural basis for Arl3 specificity.\",\n      \"method\": \"X-ray crystallography (Arl3-UNC119a and Arl2-UNC119a co-crystal structures), kinetic cargo release assays, affinity measurements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structures plus quantitative kinetic assays define molecular mechanism, single rigorous study\",\n      \"pmids\": [\"22960633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Poly-GA (C9orf72 DPR protein) co-aggregates with UNC119 in neurons; poly-GA expression strongly reduces soluble UNC119 levels; UNC119 knockdown alone inhibits dendritic branching and causes neurotoxicity similar to poly-GA; UNC119 overexpression partially rescues poly-GA toxicity, indicating loss-of-function as a contributing mechanism.\",\n      \"method\": \"Quantitative mass spectrometry, co-aggregation assays, siRNA knockdown, overexpression rescue in primary neurons, patient brain immunostaining\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS plus functional knockdown/rescue in neurons, single lab\",\n      \"pmids\": [\"25120191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Genetic epistasis: knockout of Unc119 partially rescues the GRK1 transport defect in Pde6d-knockout cone photoreceptors and restores photopic ERG b-wave amplitudes, indicating that cone transport of isoprenylated (GRK1) and acylated proteins are functionally interdependent.\",\n      \"method\": \"Double knockout mouse (Pde6d; Unc119), ERG, immunolocalization\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean double-knockout genetic epistasis with functional ERG readout, single lab\",\n      \"pmids\": [\"24664735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"High-affinity myristoylated cargo peptides from ciliary proteins (GNAT1, NPHP3, Cystin1) bind Unc119a/b with subnanomolar to low-nanomolar affinity; non-ciliary Src peptide has low (micromolar) affinity; high-affinity cargo is released exclusively by Arl3·GppNHp, while low-affinity cargo is released by both Arl2 and Arl3; X-ray structure of myristoylated NPHP3 peptide in complex with Unc119a defines the +2/+3 residue positions as determinants of binding affinity; swapping +2/+3 residues reverses affinities and partially mislocalizes NPHP3.\",\n      \"method\": \"ITC/fluorescence polarization binding assays, X-ray crystallography, site-directed mutagenesis, cell-based localization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus quantitative binding assays plus mutagenesis with cellular validation, single rigorous study\",\n      \"pmids\": [\"27481943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UNC119 sequesters myristoylated Src family kinases (SFKs) from the cytoplasm; localized Arl2/3 activity on the recycling endosome releases SFKs from UNC119; Src is then trapped on the recycling endosome electrostatically while Fyn is trapped on the Golgi by palmitoyl acyl-transferase; vesicular trafficking restores SFK enrichment at the plasma membrane; UNC119 knockdown disrupts SFK localization and signaling activity.\",\n      \"method\": \"Live-cell imaging, FRAP, siRNA knockdown, colocalization, quantitative imaging of SFK distribution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple live imaging and knockdown approaches, single lab, mechanistic spatial cycle defined\",\n      \"pmids\": [\"28740133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Squarunkin A, a small molecule inhibitor, selectively inhibits binding of myristoylated Src N-terminal peptide to UNC119A with IC50 of 10 nM; it binds UNC119 proteins in cell lysate and interferes with Src kinase activation, demonstrating the UNC119–cargo interaction is druggable.\",\n      \"method\": \"Competitive binding assay (IC50 determination), cell lysate engagement, Src kinase activity assay\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — quantitative in vitro inhibition plus cell-based kinase readout, single lab\",\n      \"pmids\": [\"28471079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UNC119 interacts with RASSF6 and promotes the RASSF6–MDM2 interaction, stabilizing p53; UNC119 induces apoptosis via RASSF6 and p53; UNC119 depletion impairs DNA repair after DNA damage and causes polyploid cell generation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, apoptosis assays, DNA damage assays (polyploidy analysis)\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CoIP plus functional loss-of-function assays, single lab\",\n      \"pmids\": [\"29931788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lipidated, hydrocarbon-stapled peptides derived from the UNC119-binding partner Gnat1 bind UNC119a and cause accumulation of cytokinetic and binucleated cells, implicating UNC119a in the completion of cytokinesis.\",\n      \"method\": \"Hydrocarbon stapling, binding assays, cell biology assays (cytokinesis/binucleation phenotype)\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological tool with phenotypic readout but indirect mechanism\",\n      \"pmids\": [\"31680402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UNC119A interacts with the active (GTP-bound) form of KRAS; the C-terminal modification of KRAS is required for this interaction; the myristoyl-binding hydrophobic pocket of UNC119A is NOT involved; UNC119A promotes KRAS binding to RASSF6, enhancing RASSF6–MDM2 interaction and p53-dependent apoptosis; UNC119A silencing promotes soft-agar colony formation, migration, and invasiveness in KRAS-mutated cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, RNAi gene silencing, immunofluorescence, cell biology assays (soft-agar colony formation, migration, invasion)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CoIP plus domain mapping plus multiple functional assays, single lab\",\n      \"pmids\": [\"32554467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deletion of one or both UNC119 alleles in mice reduces steady-state glutamate release rate at rod synapses (depolarizes rod bipolar cell membrane potential, decreases sensitivity, accelerates response decay, decreases Hill coefficient), without changing rod outer segment photocurrent or synaptic Ca2+ current voltage dependence; UNC119 facilitates glutamate release at rod ribbon synapses, likely via interaction with RIBEYE or other synaptic proteins rather than CaBP4 or calcium channels.\",\n      \"method\": \"Patch-clamp recordings from retinal slices in UNC119 heterozygous and homozygous knockout mice, bright-light transducin translocation experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiological recordings in knockout mice with multiple readouts, single lab\",\n      \"pmids\": [\"37175812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UNC119 interacts with cone-specific transducin α-subunit Gnat2 and is required for translocation of Gnat2 to the outer segment in cone photoreceptors; Unc119-deficient mice show progressive cone-rod dystrophy with activation of JAK-STAT and NF-κB inflammatory pathways; a human CRD-associated UNC119 mutant competitively inhibits the UNC119–GNAT1/GNAT2 interaction; curcumin treatment suppresses inflammation and cone degeneration in Unc119-deficient retinas.\",\n      \"method\": \"Co-immunoprecipitation, Unc119 knockout mouse, RNA-seq/bioinformatics, immunofluorescence, curcumin pharmacological rescue\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus knockout mouse with transcriptomic pathway analysis and pharmacological rescue, single lab\",\n      \"pmids\": [\"41107067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UNC119 directly traffics LCK to the immunological synapse in T cells; inhibiting UNC119 reduces LCK localization at the synapse without impairing LCK phosphorylation, and reduces TCR signal transduction; UNC119 sustains proliferation in T-ALL cells.\",\n      \"method\": \"Immunofluorescence localization, UNC119 inhibition (pharmacological), TCR signaling assays, proliferation assays in primary T cells and patient-derived T-ALL cells\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional signaling readout plus disease-relevant cell line validation, single lab\",\n      \"pmids\": [\"39814552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC119 is a lipid-binding chaperone with an immunoglobulin-like β-sandwich fold that forms a hydrophobic pocket to sequester the N-terminal myristoyl (or lauroyl) chains of diverse cargo proteins—including transducin α-subunits, Src family kinases, NPHP3, Gnat2, and LCK—shielding them from membranes and enabling their cytoplasmic diffusion; Arl3-GTP (and, for low-affinity cargo, also Arl2-GTP) allosterically displaces cargo from UNC119's hydrophobic pocket at the cilium or recycling endosome to deliver myristoylated proteins to specific membrane compartments, forming an ARL3-UNC119-RP2 GTPase cycle essential for ciliary targeting; at the photoreceptor ribbon synapse, UNC119 is recruited by RIBEYE and CaBP4 and facilitates glutamate release; in immune cells, UNC119 activates Lck/Fyn/Lyn/Abl kinases by direct interaction and traffics LCK to the immunological synapse; UNC119 also inhibits dynamin GTPase activity to regulate endocytosis and interacts with RASSF6 to promote KRAS/p53-dependent apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UNC119 is a lipid-binding chaperone that solubilizes N-terminally acylated proteins and delivers them to specific membrane compartments, a role conserved from C. elegans neurons to the mammalian photoreceptor and immune system [#0, #15]. Its immunoglobulin-like β-sandwich fold forms a hydrophobic cavity that buries the myristoyl (or lauroyl) chain of cargo such as transducin α (Gαt1/GNAT1), the cone transducin Gnat2, NPHP3, and Src-family kinases, shielding the lipid from membranes and enabling cytoplasmic diffusion; binding depends on N-acylation and on +2/+3 residue identity that tunes affinity from subnanomolar (ciliary cargo) to micromolar (Src) [#15, #16, #21]. Cargo is released by an Arl3-GTP–driven allosteric switch: although both Arl2 and Arl3 bind UNC119, only Arl3·GTP retains its N-terminal amphipathic helix surface-bound and widens the myristoyl pocket to accelerate cargo release by orders of magnitude, with high-affinity cargo released exclusively by Arl3 and low-affinity cargo by either GTPase [#18, #21]. This release occurs at the cilium, where UNC119b together with Arl3 and the Arl3-GAP RP2 forms a GTPase cycle that targets myristoylated NPHP3, and at the recycling endosome, where Arl2/3 activity liberates Src-family kinases for vesicular delivery to the plasma membrane [#17, #22]. In photoreceptors UNC119 governs light-driven transducin solubilization and translocation of Gαt1 and Gnat2 to the outer segment, and is independently recruited to the ribbon synapse by direct interaction with the RIBEYE(B) domain and stabilized by CaBP4, where it facilitates glutamate release [#16, #11, #12, #27, #28]. In immune cells UNC119 binds and activates Lck, Fyn, Lyn, and Abl kinases and traffics LCK to the immunological synapse to sustain TCR signaling and T cell proliferation [#5, #7, #29]. Beyond cargo chaperoning, UNC119 directly inhibits dynamin GTPase activity to restrain endocytosis [#13], and interacts with active KRAS and RASSF6 to stabilize p53 and promote apoptosis through a pocket-independent surface [#24, #26]. Premature-termination mutations in UNC119 cause cone-rod dystrophy, and Unc119-deficient mice develop progressive retinal degeneration with JAK-STAT and NF-κB inflammatory activation [#4, #28].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that unc-119 is a nervous-system gene required for behavior, anchoring its biology to neurons before any molecular function was known.\",\n      \"evidence\": \"unc-119/lacZ reporter, genomic rescue, and null-allele phenotyping in C. elegans\",\n      \"pmids\": [\"8582641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular activity defined\", \"Cell type of action within the nervous system not resolved at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Localized the mammalian ortholog (HRG4) to photoreceptor ribbon synapses, the first link to retinal neurotransmission.\",\n      \"evidence\": \"Immunofluorescence and EM localization plus Western blot in human and rat retina\",\n      \"pmids\": [\"9538874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional manipulation\", \"Synaptic mechanism not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the conserved C-terminal domain as the functional unit and tied a human truncation mutation to cone-rod dystrophy with a synaptic transmission defect, providing the first disease connection.\",\n      \"evidence\": \"Cross-species domain-truncation rescue in C. elegans; patient mutation screen with transgenic mouse ERG/histopathology\",\n      \"pmids\": [\"10858820\", \"11006213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of the domain function unknown\", \"Dominant mechanism of the truncation not yet explained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified ARL2 as a direct binding partner via a PDE-delta-homologous domain, first connecting UNC119 to an Arf-like GTPase.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, direct binding, and retinal colocalization\",\n      \"pmids\": [\"12527357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ARL2 binding undefined\", \"Arl2 vs Arl3 specificity not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed an immune function: UNC119 activates Src-family kinases (Lck/Fyn) downstream of CD3/CD4 to drive T cell IL-2 production and proliferation, extending its role beyond the retina.\",\n      \"evidence\": \"Reciprocal co-IP, kinase assays, and genetic reconstitution in UNC119-deficient T cells (building on IL-5Rα/Lyn work in eosinophils)\",\n      \"pmids\": [\"14757743\", \"12496276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of kinase activation unclear\", \"Relationship to lipid-binding pocket not yet known\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Explained dominant retinal disease by showing the truncated mutant binds ARL2 with higher affinity, sequestering it and triggering mitochondrial-dependent synaptic apoptosis, while knockout revealed a separate distal photoreceptor role.\",\n      \"evidence\": \"Saturation binding affinity, TUNEL/morphometry in transgenic mice, and gene-targeted knockout with ERG/histology\",\n      \"pmids\": [\"16565359\", \"17174953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo at distal vs synaptic compartments not identified\", \"Direct vs indirect role in apoptosis unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined how UNC119 is targeted to the ribbon synapse, through direct PrBP/delta-domain binding to RIBEYE(B) and stabilization by CaBP4.\",\n      \"evidence\": \"Five orthogonal binding methods with RIBEYE point mutagenesis; affinity/Y2H/co-IP plus CaBP4-KO retina analysis\",\n      \"pmids\": [\"18664567\", \"18296658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How synaptic recruitment relates to the cargo-chaperone activity unclear\", \"Functional output of synaptic UNC119 not yet measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Broadened the kinase/trafficking repertoire by showing UNC119 inhibits dynamin GTPase to restrain endocytosis and inhibits Abl kinases to limit bacterial invasion.\",\n      \"evidence\": \"Co-IP, GTPase and kinase assays, multi-cargo uptake assays, and an in vivo shigellosis mouse model\",\n      \"pmids\": [\"19781630\", \"19381274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of dynamin/Abl inhibition unknown\", \"Whether these activities share the lipid pocket undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the core molecular mechanism: UNC119 is a myristoyl-binding chaperone with an Ig-like β-sandwich pocket that sequesters acylated transducin α and is required for G protein localization.\",\n      \"evidence\": \"Apo and co-crystal X-ray structures, ITC, GTPase assays, and mouse/C. elegans knockouts; parallel human biochemistry showing acyl-dependent Gαt binding and transducin solubilization\",\n      \"pmids\": [\"21642972\", \"21712387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo-release trigger not yet defined\", \"Conflicting effects on Gαt GTPase between studies\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed UNC119 in a ciliary delivery cycle by showing UNC119b carries myristoylated NPHP3 and that Arl3-GTP releases cargo within an ARL3–UNC119b–RP2 GTPase module.\",\n      \"evidence\": \"Proteomics, mutagenesis with structural modeling, ciliary targeting assays, and C. elegans genetics\",\n      \"pmids\": [\"22085962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only UNC119b functions in ciliary NPHP3 targeting unexplained at structural level\", \"Isoform-specific cargo repertoire incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the structural basis of Arl3 specificity: only Arl3-GTP keeps its amphipathic helix surface-bound and widens the myristoyl pocket to accelerate cargo release ~1000-fold, distinguishing it from Arl2.\",\n      \"evidence\": \"Co-crystal structures of Arl3- and Arl2-UNC119a with kinetic release and affinity assays\",\n      \"pmids\": [\"22960633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo compartment where each GTPase acts not yet mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a cargo affinity code: +2/+3 residues set subnanomolar (ciliary) versus micromolar (Src) affinity, dictating whether cargo is released only by Arl3 or by both Arl2 and Arl3.\",\n      \"evidence\": \"ITC/FP binding, NPHP3-peptide co-crystal, and residue-swap mutagenesis with cellular localization\",\n      \"pmids\": [\"27481943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full cargo set across tissues not enumerated\", \"How affinity maps to compartment specificity in vivo only partly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked UNC119-dependent acyl-cargo transport to prenyl-cargo transport, showing Unc119 loss partially rescues the GRK1 defect of Pde6d-knockout cones.\",\n      \"evidence\": \"Pde6d;Unc119 double-knockout mice with ERG and immunolocalization\",\n      \"pmids\": [\"24664735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the UNC119/PDE6D crosstalk unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed how the chaperone integrates with membrane trafficking: localized Arl2/3 activity on recycling endosomes releases Src-family kinases from UNC119 for compartment-specific re-targeting, and that the cargo interaction is druggable.\",\n      \"evidence\": \"Live imaging/FRAP/knockdown of SFK distribution; competitive small-molecule inhibitor (Squarunkin A, 10 nM) with cell-based kinase readout\",\n      \"pmids\": [\"28740133\", \"28471079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous spatial regulators of Arl activity not identified\", \"Therapeutic relevance of inhibition untested in disease models\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a non-canonical tumor-suppressive role through RASSF6-MDM2-p53 signaling and a DNA-damage/ploidy phenotype, separate from cargo chaperoning.\",\n      \"evidence\": \"Reciprocal co-IP, knockdown, apoptosis and polyploidy assays\",\n      \"pmids\": [\"29931788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role in DNA repair unclear\", \"Connection to the lipid pocket not addressed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed UNC119A engages active KRAS through a pocket-independent surface and bridges KRAS-RASSF6-MDM2 to promote p53-dependent apoptosis, defining a tumor-suppressive axis in KRAS-mutant cancer.\",\n      \"evidence\": \"Co-IP with domain mapping, RNAi silencing, and soft-agar/migration/invasion assays\",\n      \"pmids\": [\"32554467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of KRAS binding unknown\", \"Whether this competes with lipid-cargo function in cells untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided direct functional evidence that synaptic UNC119 sets the rate of glutamate release at rod ribbon synapses, independent of CaBP4 or calcium channels.\",\n      \"evidence\": \"Patch-clamp from retinal slices of Unc119 heterozygous and homozygous knockout mice\",\n      \"pmids\": [\"37175812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism coupling UNC119 to release machinery undefined\", \"Which synaptic partner mediates the effect unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the cargo and disease picture: UNC119 carries cone transducin Gnat2 to the outer segment, its loss drives inflammatory cone-rod dystrophy via JAK-STAT/NF-κB, and it traffics LCK to the immunological synapse to sustain T-ALL proliferation.\",\n      \"evidence\": \"Co-IP, Unc119-knockout mice with RNA-seq and curcumin rescue; immunofluorescence and TCR/proliferation assays in primary and T-ALL cells\",\n      \"pmids\": [\"41107067\", \"39814552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking cargo mislocalization to inflammatory signaling unclear\", \"How LCK trafficking by UNC119 integrates with prior SFK-activation data not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UNC119's distinct activities — myristoyl-cargo chaperoning, kinase activation, dynamin inhibition, synaptic glutamate release, and KRAS/RASSF6/p53 signaling — are coordinated within a single protein, and whether they share or partition structural surfaces, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking pocket-dependent and pocket-independent functions\", \"Isoform-specific (UNC119a vs UNC119b) division of labor only partly mapped\", \"Physiological cargo set across non-retinal tissues incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [15, 16, 17, 21]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [15, 16, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 13, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [17, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 16, 22]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [17, 21]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [17, 22, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 26, 29]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 22]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [16, 27, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 29]}\n    ],\n    \"complexes\": [\"ARL3-UNC119b-RP2 ciliary GTPase cycle\"],\n    \"partners\": [\"ARL3\", \"ARL2\", \"GNAT1\", \"GNAT2\", \"NPHP3\", \"RIBEYE\", \"LCK\", \"KRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}