{"gene":"NEURL4","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2012,"finding":"NEURL4 localizes to centrosomes (procentrioles and daughter centrioles via its Neuralized homology repeat) and promotes ubiquitylation of CP110, thereby destabilizing CP110 and preventing the formation of ectopic microtubule organizing centres (MTOCs). Depletion of Neurl4 causes ectopic MTOCs, accumulation of CP110, and assembly of aberrant mitotic spindles.","method":"RNA interference (siRNA depletion), high-resolution imaging, ubiquitylation assay, structure-function analysis with domain mutants","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined cellular phenotype, ubiquitylation assay, and replicated across two independent labs (PMID:22441691 and PMID:22261722) using orthogonal methods","pmids":["22441691"],"is_preprint":false},{"year":2012,"finding":"NEURL4 interacts with the centrosomal protein CP110 and with the E3 ligase HERC2; these interactions require non-overlapping regions of NEURL4. The NEURL4–HERC2 complex regulates centrosome architecture: depletion of either HERC2 or NEURL4 produces aberrant filamentous structures at the centrosome that stain for pericentrin and CEP135. NEURL4 is itself a substrate of HERC2. CP110 binding to NEURL4 is dispensable for pericentriolar material (PCM) architecture, but the HERC2–NEURL4 association is required for normal centrosome integrity.","method":"Interaction proteomics (AP-MS), co-immunoprecipitation, RNAi knockdown, high-resolution fluorescence imaging, structure-function analysis with truncation mutants","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction proteomics confirmed by reciprocal Co-IP, structure-function dissection, multiple orthogonal readouts in one rigorous study","pmids":["22261722"],"is_preprint":false},{"year":2012,"finding":"NEURL4 is a component of a high-molecular-weight complex containing HERC2 and MAPK6, and also associates with the E3 ubiquitin ligase E6AP (UBE3A). E6AP interacts with this HERC2-containing complex through E6 binding to E6AP.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation validation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS confirmed by co-IP, single lab, two orthogonal methods","pmids":["22645313"],"is_preprint":false},{"year":2015,"finding":"LRRK2 binds to NEURL4 via its ROC domain; NEURL4 in turn connects to HERC2. The LRRK2–NEURL4–HERC2 complex promotes recycling of the Notch ligand Delta-like 1 (Dll1) through modulation of endosomal trafficking, thereby negatively regulating Notch signaling via cis-inhibition and accelerating neural stem cell differentiation.","method":"Co-immunoprecipitation, domain mapping, cell-based trafficking assays, in vivo Drosophila genetics, fluorescence imaging","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and cell-based functional assay, single lab","pmids":["26355680"],"is_preprint":false},{"year":2017,"finding":"NEURL4 directly interacts with p53 through the C-terminal region of p53 and neuralized domains 3 and 4 of NEURL4. Through this interaction, NEURL4 regulates p53 oligomerization (tetramerization) and transcriptional activity: NEURL4 depletion reduces p53 transcriptional activity while overexpression increases it, without affecting p53 protein stability. Both NEURL4 and HERC2 are needed for full regulation of p53 activity.","method":"Co-immunoprecipitation, domain-mapping with truncation mutants, luciferase reporter assay, clonogenic assay, Western blotting, siRNA knockdown and overexpression","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, reporter assays, and functional cellular readouts, single lab","pmids":["28977907"],"is_preprint":false},{"year":2017,"finding":"Neuronal RNF8 interacts with HERC2 and scaffold protein NEURL4 in the cytoplasm; knockdown of HERC2 or NEURL4 phenocopies RNF8/UBC13 loss-of-function by increasing the number of presynaptic boutons and functional parallel fiber/Purkinje cell synapses, placing NEURL4 in an RNF8–UBC13 cytoplasmic ubiquitin-signaling network that suppresses synapse formation in cerebellar neurons.","method":"Proteomics (AP-MS), in vivo RNAi knockdown in rodent cerebellum, conditional knockout, electrophysiology, confocal imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics confirmed by in vivo genetic epistasis (KD phenocopy), multiple orthogonal methods, defined cellular phenotype","pmids":["29097665"],"is_preprint":false},{"year":2019,"finding":"NEURL4 and HERC2 form a complex with oligomeric p53 and MDM2. DNA damage (bleomycin) dissociates MDM2 from the p53/HERC2/NEURL4 complex, increases phosphorylation and acetylation of oligomeric p53 bound to HERC2/NEURL4, and the MDM2 promoter competes with HERC2 for binding of this modified p53 form. HERC2 knockdown reduces MDM2 mRNA/protein levels by inhibiting MDM2 promoter activation.","method":"Co-immunoprecipitation, siRNA knockdown, promoter reporter assay, Western blotting, RT-PCR","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA KD with transcriptional readout, reporter assay; single lab, multiple orthogonal methods","pmids":["31665549"],"is_preprint":false},{"year":2022,"finding":"NEURL4 functions as a mitochondrial ADP-ribosyltransferase (ART) enzyme. Most ART activity associated with mitochondria is lost in the absence of NEURL4. The NEURL4-dependent ADP-ribosylome in mitochondria includes numerous previously reported ADP-ribosylated mitochondrial proteins. Specifically, NEURL4 is required for poly-ADP-ribosylation of mtLIG3 (the rate-limiting BER enzyme), thereby regulating mtDNA integrity via the base excision repair pathway.","method":"In vitro ART activity assay with mitochondrial extracts, NEURL4 knockout/knockdown, mass spectrometry-based ADP-ribosylome mapping, functional mtDNA integrity assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic activity reconstitution, ADP-ribosylome MS in KO vs WT, specific substrate (mtLIG3) identified with functional readout (mtDNA BER), multiple orthogonal methods in one rigorous study","pmids":["35157000"],"is_preprint":false},{"year":2015,"finding":"In Drosophila, Neurl4 is concentrated at centrosomes and downregulates CP110 levels. Reducing CP110 activity suppresses the abnormal primordial germ cell (PGC) morphology caused by Neurl4 loss-of-function, establishing a genetic epistasis relationship in which Neurl4 acts upstream of CP110 to maintain PGC integrity. Neurl4 also has a separate role in germ plasm formation during oogenesis.","method":"Drosophila genetics (loss-of-function mutants), genetic epistasis (double mutant suppressor analysis), immunofluorescence imaging","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo (CP110 suppresses Neurl4 mutant PGC phenotype), direct localization, ortholog study consistent with mammalian findings","pmids":["26116656"],"is_preprint":false},{"year":2023,"finding":"NEURL4 mediates CP110 degradation via the ubiquitin-dependent proteasome pathway to remove the inhibitory centriolar cap and allow primary cilia biogenesis. Overexpression of NEURL4 is sufficient to promote primary cilia formation and reduce CP110 levels at centrioles. ODF2 acts upstream of NEURL4, likely as a scaffold for NEURL4 recruitment to the centriole.","method":"RNAi knockdown of ODF2, overexpression of NEURL4 and HYLS1, rapamycin-mediated dimerization for centriolar recruitment, immunofluorescence imaging of CP110 levels and cilia","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression gain-of-function and KD with defined organelle phenotype (cilia formation, CP110 levels), single lab","pmids":["37681926"],"is_preprint":false},{"year":2009,"finding":"The NMR solution structure of the Drosophila Neuralized NHR1 domain was determined, revealing a beta-sandwich fold similar to B30.2/SPRY domains. Comparison with the first NHR domain of human KIAA1787 (NEURL4), which belongs to a different NHR subfamily, identified critical residues responsible for the NHR1–Tom peptide interaction specificity, and confirmed that NEURL4's NHR domain does not bind the Tom peptide (negative result for this interaction).","method":"Heteronuclear NMR structure determination, isothermal titration calorimetry (ITC), NMR titration experiments, cell-free protein synthesis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-quality NMR structure with ITC validation for Drosophila Neur NHR1; comparison to human NEURL4 NHR domain is structural/sequence-based without functional validation of the human domain","pmids":["19683535"],"is_preprint":false}],"current_model":"NEURL4 is a multifunctional scaffold/enzyme that (1) acts as the principal mitochondrial ADP-ribosyltransferase, poly-ADP-ribosylating mtLIG3 to regulate mtDNA base excision repair; (2) localizes to daughter/procentrioles where it promotes CP110 ubiquitylation and degradation—working within a NEURL4–HERC2 complex—to maintain centrosome architecture and prevent ectopic MTOC formation and to permit primary cilia biogenesis; (3) modulates p53 oligomerization and transcriptional activity through direct interaction with the p53 C-terminus via its NHR domains 3–4, cooperating with HERC2 and MDM2 in the p53 regulatory loop; and (4) participates in a cytoplasmic RNF8–UBC13–HERC2–NEURL4 ubiquitin-signaling network that suppresses synapse formation in neurons, and in a LRRK2–NEURL4–HERC2 complex that modulates endosomal trafficking of Notch ligand Dll1."},"narrative":{"mechanistic_narrative":"NEURL4 is a multidomain scaffold and enzyme that operates at centrosomes, in mitochondria, and within HERC2-centered ubiquitin-signaling networks to control centriole homeostasis, genome integrity, and cell-fate signaling [PMID:22441691, PMID:35157000, PMID:29097665]. At the centrosome, NEURL4 localizes to procentrioles and daughter centrioles through its Neuralized homology repeat and drives ubiquitylation and destabilization of the centriolar capping protein CP110; its loss causes CP110 accumulation, ectopic microtubule organizing centres, and aberrant mitotic spindles [PMID:22441691]. This CP110-removing activity is recruited to the centriole by ODF2 and is sufficient to license primary cilia biogenesis [PMID:37681926], and the upstream Neurl4→CP110 epistasis is conserved in Drosophila where it maintains primordial germ cell integrity [PMID:26116656]. NEURL4 physically engages the E3 ligase HERC2—being itself a HERC2 substrate—through a region distinct from its CP110-binding site, and the HERC2–NEURL4 association is required for normal centrosome and pericentriolar material architecture [PMID:22261722]. Beyond the centrosome, NEURL4 directly binds the p53 C-terminus via its Neuralized domains 3 and 4 to promote p53 tetramerization and transcriptional activity without altering p53 stability, acting with HERC2 and MDM2 in a DNA-damage-responsive regulatory complex [PMID:28977907, PMID:31665549]. NEURL4 also participates in a cytoplasmic RNF8–UBC13–HERC2 ubiquitin-signaling network that suppresses synapse formation in cerebellar neurons [PMID:29097665] and in a LRRK2–NEURL4–HERC2 complex that modulates endosomal recycling of the Notch ligand Dll1 to regulate neural stem cell differentiation [PMID:26355680]. Independently of these scaffolding roles, NEURL4 is the principal mitochondrial ADP-ribosyltransferase, accounting for most mitochondrial ART activity and poly-ADP-ribosylating the base excision repair ligase mtLIG3 to maintain mtDNA integrity [PMID:35157000].","teleology":[{"year":2009,"claim":"Establishing the structural basis of Neuralized homology repeats addressed how these domains recognize ligands and showed that the human NEURL4 NHR domain belongs to a distinct subfamily that does not bind the Tom peptide.","evidence":"NMR solution structure of Drosophila Neur NHR1 with ITC, compared to human NEURL4 NHR1","pmids":["19683535"],"confidence":"Medium","gaps":["Human NEURL4 NHR domain function was inferred structurally without functional validation","No NEURL4 ligand identified by this structural comparison","Full-length NEURL4 architecture not resolved"]},{"year":2012,"claim":"Discovery that NEURL4 localizes to centrioles and promotes CP110 ubiquitylation defined its first cellular function: preventing ectopic MTOC formation and preserving spindle and centrosome integrity.","evidence":"siRNA depletion, ubiquitylation assays, domain mutants, and AP-MS/Co-IP defining NEURL4–CP110 and NEURL4–HERC2 interactions in human cells","pmids":["22441691","22261722"],"confidence":"High","gaps":["The catalytic identity of the ligase directly ubiquitylating CP110 within the complex not pinned down","Whether NEURL4 acts as adaptor or has intrinsic enzymatic role at the centrosome unresolved at this stage"]},{"year":2012,"claim":"Mapping NEURL4 into a high-molecular-weight HERC2–MAPK6 complex that also associates with E6AP/UBE3A placed it within a broader ubiquitin-regulatory assembly.","evidence":"Affinity purification/mass spectrometry with Co-IP validation, single lab","pmids":["22645313"],"confidence":"Medium","gaps":["Functional consequence of the MAPK6 and E6AP associations not established","Stoichiometry and architecture of the complex unknown"]},{"year":2015,"claim":"Identifying the LRRK2–NEURL4–HERC2 complex connected NEURL4 to endosomal trafficking, showing it modulates Dll1 recycling to negatively regulate Notch and accelerate neural stem cell differentiation.","evidence":"Co-IP, domain mapping, cell-based trafficking assays, and Drosophila genetics, single lab","pmids":["26355680"],"confidence":"Medium","gaps":["Direct mechanism linking the complex to endosomal sorting machinery unclear","Whether ubiquitin transfer onto trafficking cargo is involved not shown"]},{"year":2015,"claim":"Conservation of the Neurl4→CP110 epistasis in Drosophila confirmed CP110 downregulation as the core ancestral function and extended it to germ cell biology.","evidence":"Drosophila loss-of-function genetics and double-mutant suppressor analysis with immunofluorescence","pmids":["26116656"],"confidence":"Medium","gaps":["The germ plasm role appears separable from CP110 regulation and remains mechanistically undefined","Molecular link between CP110 control and PGC morphology not detailed"]},{"year":2017,"claim":"Demonstrating direct NEURL4–p53 binding via NHR domains 3–4 revealed a non-degradative role: NEURL4 promotes p53 tetramerization and transcriptional output, expanding its function into tumor-suppressor signaling.","evidence":"Co-IP, domain mapping, luciferase reporter and clonogenic assays, knockdown/overexpression, single lab","pmids":["28977907"],"confidence":"Medium","gaps":["Structural basis of how NEURL4 binding favors p53 tetramers not resolved","Whether HERC2 ubiquitin activity contributes mechanistically unclear"]},{"year":2017,"claim":"Placing NEURL4 within the neuronal cytoplasmic RNF8–UBC13–HERC2 network established its role in suppressing synapse formation in cerebellum.","evidence":"AP-MS, in vivo RNAi, conditional knockout, electrophysiology, and confocal imaging with genetic epistasis (KD phenocopy)","pmids":["29097665"],"confidence":"High","gaps":["Synaptic substrate(s) ubiquitylated by this network not identified","How a cytoplasmic ubiquitin signal limits bouton number mechanistically unknown"]},{"year":2019,"claim":"Defining a DNA-damage-responsive p53/HERC2/NEURL4/MDM2 complex showed how NEURL4-bound oligomeric p53 is modified and partitioned between HERC2 and the MDM2 promoter, linking the scaffold to the p53–MDM2 feedback loop.","evidence":"Co-IP, siRNA knockdown, promoter reporter assays, Western blot, and RT-PCR after bleomycin treatment","pmids":["31665549"],"confidence":"Medium","gaps":["Direct contribution of NEURL4 (versus HERC2) to MDM2 promoter regulation not separated","Kinetics of complex dissociation after DNA damage incompletely defined"]},{"year":2022,"claim":"Identifying NEURL4 as the principal mitochondrial ADP-ribosyltransferase that poly-ADP-ribosylates mtLIG3 defined an enzymatic, organelle-specific function in mtDNA base excision repair, distinct from its scaffolding roles.","evidence":"In vitro ART activity assays on mitochondrial extracts, NEURL4 KO/KD, ADP-ribosylome mass spectrometry, and mtDNA integrity readout","pmids":["35157000"],"confidence":"High","gaps":["Catalytic domain/residues mediating ART activity within NEURL4 not mapped","How NEURL4 enzymatic activity is regulated and coordinated with its centrosomal/nuclear roles unknown"]},{"year":null,"claim":"How NEURL4 partitions and coordinates its distinct enzymatic (mitochondrial ART) and scaffolding (centrosomal, p53, synaptic, trafficking) activities, and which domains confer each, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length human NEURL4 or its catalytic ART module","No unified model linking subcellular pools to specific functions","Regulation of NEURL4 by its own HERC2-mediated ubiquitylation across compartments unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5]}],"complexes":["NEURL4–HERC2 complex","LRRK2–NEURL4–HERC2 complex","RNF8–UBC13–HERC2–NEURL4 network","p53/HERC2/NEURL4/MDM2 complex"],"partners":["HERC2","CP110","TP53","MDM2","LRRK2","RNF8","ODF2","MAPK6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JN8","full_name":"Neuralized-like protein 4","aliases":[],"length_aa":1562,"mass_kda":166.9,"function":"Promotes CCP110 ubiquitination and proteasome-dependent degradation. By counteracting accumulation of CP110, maintains normal centriolar homeostasis and preventing formation of ectopic microtubular organizing centers","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q96JN8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NEURL4","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NEURL4","total_profiled":1310},"omim":[{"mim_id":"618832","title":"EPILEPSY, EARLY-ONSET, 2, WITH OR WITHOUT DEVELOPMENTAL DELAY; EPEO2","url":"https://www.omim.org/entry/618832"},{"mim_id":"615865","title":"NEURALIZED E3 UBIQUITIN PROTEIN LIGASE 4; NEURL4","url":"https://www.omim.org/entry/615865"},{"mim_id":"611052","title":"SET DOMAIN-CONTAINING PROTEIN 1A; SETD1A","url":"https://www.omim.org/entry/611052"},{"mim_id":"609544","title":"CENTRIOLAR COILED-COIL PROTEIN, 110-KD; CCP110","url":"https://www.omim.org/entry/609544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NEURL4"},"hgnc":{"alias_symbol":["KIAA1787"],"prev_symbol":[]},"alphafold":{"accession":"Q96JN8","domains":[{"cath_id":"2.60.120.920","chopping":"45-205","consensus_level":"high","plddt":91.3216,"start":45,"end":205},{"cath_id":"2.60.120.920","chopping":"329-487","consensus_level":"high","plddt":88.4565,"start":329,"end":487},{"cath_id":"2.60.120.920","chopping":"524-684","consensus_level":"high","plddt":89.8693,"start":524,"end":684},{"cath_id":"2.60.120.920","chopping":"720-882","consensus_level":"high","plddt":88.984,"start":720,"end":882},{"cath_id":"2.60.120.920","chopping":"917-981_997-1084","consensus_level":"high","plddt":89.9795,"start":917,"end":1084},{"cath_id":"2.60.120.920","chopping":"1135-1293","consensus_level":"high","plddt":89.2252,"start":1135,"end":1293},{"cath_id":"3.90.228","chopping":"1339-1443_1475-1562","consensus_level":"high","plddt":84.7034,"start":1339,"end":1562}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JN8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JN8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JN8-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NEURL4","jax_strain_url":"https://www.jax.org/strain/search?query=NEURL4"},"sequence":{"accession":"Q96JN8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JN8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JN8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JN8"}},"corpus_meta":[{"pmid":"22645313","id":"PMC_22645313","title":"Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22645313","citation_count":88,"is_preprint":false},{"pmid":"22399070","id":"PMC_22399070","title":"Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions.","date":"2012","source":"Molecular bioSystems","url":"https://pubmed.ncbi.nlm.nih.gov/22399070","citation_count":62,"is_preprint":false},{"pmid":"22261722","id":"PMC_22261722","title":"Interaction proteomics identify NEURL4 and the HECT E3 ligase HERC2 as novel modulators of centrosome architecture.","date":"2012","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/22261722","citation_count":60,"is_preprint":false},{"pmid":"26355680","id":"PMC_26355680","title":"The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal 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of the MDM2-p53 pathway by the ubiquitin ligase HERC2.","date":"2019","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31665549","citation_count":34,"is_preprint":false},{"pmid":"31817155","id":"PMC_31817155","title":"Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31817155","citation_count":27,"is_preprint":false},{"pmid":"19683535","id":"PMC_19683535","title":"Structural and functional characterization of the NHR1 domain of the Drosophila neuralized E3 ligase in the notch signaling pathway.","date":"2009","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19683535","citation_count":23,"is_preprint":false},{"pmid":"28977907","id":"PMC_28977907","title":"NEURL4 regulates the transcriptional activity of tumor suppressor protein p53 by modulating its 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thyroid hormones and prostate cancer: insights from NHANES, Mendelian randomization, genetic markers, and bioinformatics analyses.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40397285","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11120,"output_tokens":3304,"usd":0.04146,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10773,"output_tokens":3958,"usd":0.076408,"stage2_stop_reason":"end_turn"},"total_usd":0.117868,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"NEURL4 localizes to centrosomes (procentrioles and daughter centrioles via its Neuralized homology repeat) and promotes ubiquitylation of CP110, thereby destabilizing CP110 and preventing the formation of ectopic microtubule organizing centres (MTOCs). Depletion of Neurl4 causes ectopic MTOCs, accumulation of CP110, and assembly of aberrant mitotic spindles.\",\n      \"method\": \"RNA interference (siRNA depletion), high-resolution imaging, ubiquitylation assay, structure-function analysis with domain mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined cellular phenotype, ubiquitylation assay, and replicated across two independent labs (PMID:22441691 and PMID:22261722) using orthogonal methods\",\n      \"pmids\": [\"22441691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NEURL4 interacts with the centrosomal protein CP110 and with the E3 ligase HERC2; these interactions require non-overlapping regions of NEURL4. The NEURL4–HERC2 complex regulates centrosome architecture: depletion of either HERC2 or NEURL4 produces aberrant filamentous structures at the centrosome that stain for pericentrin and CEP135. NEURL4 is itself a substrate of HERC2. CP110 binding to NEURL4 is dispensable for pericentriolar material (PCM) architecture, but the HERC2–NEURL4 association is required for normal centrosome integrity.\",\n      \"method\": \"Interaction proteomics (AP-MS), co-immunoprecipitation, RNAi knockdown, high-resolution fluorescence imaging, structure-function analysis with truncation mutants\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction proteomics confirmed by reciprocal Co-IP, structure-function dissection, multiple orthogonal readouts in one rigorous study\",\n      \"pmids\": [\"22261722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NEURL4 is a component of a high-molecular-weight complex containing HERC2 and MAPK6, and also associates with the E3 ubiquitin ligase E6AP (UBE3A). E6AP interacts with this HERC2-containing complex through E6 binding to E6AP.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation validation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS confirmed by co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"22645313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LRRK2 binds to NEURL4 via its ROC domain; NEURL4 in turn connects to HERC2. The LRRK2–NEURL4–HERC2 complex promotes recycling of the Notch ligand Delta-like 1 (Dll1) through modulation of endosomal trafficking, thereby negatively regulating Notch signaling via cis-inhibition and accelerating neural stem cell differentiation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, cell-based trafficking assays, in vivo Drosophila genetics, fluorescence imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and cell-based functional assay, single lab\",\n      \"pmids\": [\"26355680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NEURL4 directly interacts with p53 through the C-terminal region of p53 and neuralized domains 3 and 4 of NEURL4. Through this interaction, NEURL4 regulates p53 oligomerization (tetramerization) and transcriptional activity: NEURL4 depletion reduces p53 transcriptional activity while overexpression increases it, without affecting p53 protein stability. Both NEURL4 and HERC2 are needed for full regulation of p53 activity.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping with truncation mutants, luciferase reporter assay, clonogenic assay, Western blotting, siRNA knockdown and overexpression\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, reporter assays, and functional cellular readouts, single lab\",\n      \"pmids\": [\"28977907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Neuronal RNF8 interacts with HERC2 and scaffold protein NEURL4 in the cytoplasm; knockdown of HERC2 or NEURL4 phenocopies RNF8/UBC13 loss-of-function by increasing the number of presynaptic boutons and functional parallel fiber/Purkinje cell synapses, placing NEURL4 in an RNF8–UBC13 cytoplasmic ubiquitin-signaling network that suppresses synapse formation in cerebellar neurons.\",\n      \"method\": \"Proteomics (AP-MS), in vivo RNAi knockdown in rodent cerebellum, conditional knockout, electrophysiology, confocal imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics confirmed by in vivo genetic epistasis (KD phenocopy), multiple orthogonal methods, defined cellular phenotype\",\n      \"pmids\": [\"29097665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NEURL4 and HERC2 form a complex with oligomeric p53 and MDM2. DNA damage (bleomycin) dissociates MDM2 from the p53/HERC2/NEURL4 complex, increases phosphorylation and acetylation of oligomeric p53 bound to HERC2/NEURL4, and the MDM2 promoter competes with HERC2 for binding of this modified p53 form. HERC2 knockdown reduces MDM2 mRNA/protein levels by inhibiting MDM2 promoter activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, promoter reporter assay, Western blotting, RT-PCR\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA KD with transcriptional readout, reporter assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31665549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NEURL4 functions as a mitochondrial ADP-ribosyltransferase (ART) enzyme. Most ART activity associated with mitochondria is lost in the absence of NEURL4. The NEURL4-dependent ADP-ribosylome in mitochondria includes numerous previously reported ADP-ribosylated mitochondrial proteins. Specifically, NEURL4 is required for poly-ADP-ribosylation of mtLIG3 (the rate-limiting BER enzyme), thereby regulating mtDNA integrity via the base excision repair pathway.\",\n      \"method\": \"In vitro ART activity assay with mitochondrial extracts, NEURL4 knockout/knockdown, mass spectrometry-based ADP-ribosylome mapping, functional mtDNA integrity assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic activity reconstitution, ADP-ribosylome MS in KO vs WT, specific substrate (mtLIG3) identified with functional readout (mtDNA BER), multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"35157000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Drosophila, Neurl4 is concentrated at centrosomes and downregulates CP110 levels. Reducing CP110 activity suppresses the abnormal primordial germ cell (PGC) morphology caused by Neurl4 loss-of-function, establishing a genetic epistasis relationship in which Neurl4 acts upstream of CP110 to maintain PGC integrity. Neurl4 also has a separate role in germ plasm formation during oogenesis.\",\n      \"method\": \"Drosophila genetics (loss-of-function mutants), genetic epistasis (double mutant suppressor analysis), immunofluorescence imaging\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo (CP110 suppresses Neurl4 mutant PGC phenotype), direct localization, ortholog study consistent with mammalian findings\",\n      \"pmids\": [\"26116656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NEURL4 mediates CP110 degradation via the ubiquitin-dependent proteasome pathway to remove the inhibitory centriolar cap and allow primary cilia biogenesis. Overexpression of NEURL4 is sufficient to promote primary cilia formation and reduce CP110 levels at centrioles. ODF2 acts upstream of NEURL4, likely as a scaffold for NEURL4 recruitment to the centriole.\",\n      \"method\": \"RNAi knockdown of ODF2, overexpression of NEURL4 and HYLS1, rapamycin-mediated dimerization for centriolar recruitment, immunofluorescence imaging of CP110 levels and cilia\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression gain-of-function and KD with defined organelle phenotype (cilia formation, CP110 levels), single lab\",\n      \"pmids\": [\"37681926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The NMR solution structure of the Drosophila Neuralized NHR1 domain was determined, revealing a beta-sandwich fold similar to B30.2/SPRY domains. Comparison with the first NHR domain of human KIAA1787 (NEURL4), which belongs to a different NHR subfamily, identified critical residues responsible for the NHR1–Tom peptide interaction specificity, and confirmed that NEURL4's NHR domain does not bind the Tom peptide (negative result for this interaction).\",\n      \"method\": \"Heteronuclear NMR structure determination, isothermal titration calorimetry (ITC), NMR titration experiments, cell-free protein synthesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-quality NMR structure with ITC validation for Drosophila Neur NHR1; comparison to human NEURL4 NHR domain is structural/sequence-based without functional validation of the human domain\",\n      \"pmids\": [\"19683535\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NEURL4 is a multifunctional scaffold/enzyme that (1) acts as the principal mitochondrial ADP-ribosyltransferase, poly-ADP-ribosylating mtLIG3 to regulate mtDNA base excision repair; (2) localizes to daughter/procentrioles where it promotes CP110 ubiquitylation and degradation—working within a NEURL4–HERC2 complex—to maintain centrosome architecture and prevent ectopic MTOC formation and to permit primary cilia biogenesis; (3) modulates p53 oligomerization and transcriptional activity through direct interaction with the p53 C-terminus via its NHR domains 3–4, cooperating with HERC2 and MDM2 in the p53 regulatory loop; and (4) participates in a cytoplasmic RNF8–UBC13–HERC2–NEURL4 ubiquitin-signaling network that suppresses synapse formation in neurons, and in a LRRK2–NEURL4–HERC2 complex that modulates endosomal trafficking of Notch ligand Dll1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NEURL4 is a multidomain scaffold and enzyme that operates at centrosomes, in mitochondria, and within HERC2-centered ubiquitin-signaling networks to control centriole homeostasis, genome integrity, and cell-fate signaling [#0, #7, #5]. At the centrosome, NEURL4 localizes to procentrioles and daughter centrioles through its Neuralized homology repeat and drives ubiquitylation and destabilization of the centriolar capping protein CP110; its loss causes CP110 accumulation, ectopic microtubule organizing centres, and aberrant mitotic spindles [#0]. This CP110-removing activity is recruited to the centriole by ODF2 and is sufficient to license primary cilia biogenesis [#9], and the upstream Neurl4→CP110 epistasis is conserved in Drosophila where it maintains primordial germ cell integrity [#8]. NEURL4 physically engages the E3 ligase HERC2—being itself a HERC2 substrate—through a region distinct from its CP110-binding site, and the HERC2–NEURL4 association is required for normal centrosome and pericentriolar material architecture [#1]. Beyond the centrosome, NEURL4 directly binds the p53 C-terminus via its Neuralized domains 3 and 4 to promote p53 tetramerization and transcriptional activity without altering p53 stability, acting with HERC2 and MDM2 in a DNA-damage-responsive regulatory complex [#4, #6]. NEURL4 also participates in a cytoplasmic RNF8–UBC13–HERC2 ubiquitin-signaling network that suppresses synapse formation in cerebellar neurons [#5] and in a LRRK2–NEURL4–HERC2 complex that modulates endosomal recycling of the Notch ligand Dll1 to regulate neural stem cell differentiation [#3]. Independently of these scaffolding roles, NEURL4 is the principal mitochondrial ADP-ribosyltransferase, accounting for most mitochondrial ART activity and poly-ADP-ribosylating the base excision repair ligase mtLIG3 to maintain mtDNA integrity [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing the structural basis of Neuralized homology repeats addressed how these domains recognize ligands and showed that the human NEURL4 NHR domain belongs to a distinct subfamily that does not bind the Tom peptide.\",\n      \"evidence\": \"NMR solution structure of Drosophila Neur NHR1 with ITC, compared to human NEURL4 NHR1\",\n      \"pmids\": [\"19683535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Human NEURL4 NHR domain function was inferred structurally without functional validation\",\n        \"No NEURL4 ligand identified by this structural comparison\",\n        \"Full-length NEURL4 architecture not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that NEURL4 localizes to centrioles and promotes CP110 ubiquitylation defined its first cellular function: preventing ectopic MTOC formation and preserving spindle and centrosome integrity.\",\n      \"evidence\": \"siRNA depletion, ubiquitylation assays, domain mutants, and AP-MS/Co-IP defining NEURL4–CP110 and NEURL4–HERC2 interactions in human cells\",\n      \"pmids\": [\"22441691\", \"22261722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The catalytic identity of the ligase directly ubiquitylating CP110 within the complex not pinned down\",\n        \"Whether NEURL4 acts as adaptor or has intrinsic enzymatic role at the centrosome unresolved at this stage\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping NEURL4 into a high-molecular-weight HERC2–MAPK6 complex that also associates with E6AP/UBE3A placed it within a broader ubiquitin-regulatory assembly.\",\n      \"evidence\": \"Affinity purification/mass spectrometry with Co-IP validation, single lab\",\n      \"pmids\": [\"22645313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the MAPK6 and E6AP associations not established\",\n        \"Stoichiometry and architecture of the complex unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying the LRRK2–NEURL4–HERC2 complex connected NEURL4 to endosomal trafficking, showing it modulates Dll1 recycling to negatively regulate Notch and accelerate neural stem cell differentiation.\",\n      \"evidence\": \"Co-IP, domain mapping, cell-based trafficking assays, and Drosophila genetics, single lab\",\n      \"pmids\": [\"26355680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism linking the complex to endosomal sorting machinery unclear\",\n        \"Whether ubiquitin transfer onto trafficking cargo is involved not shown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conservation of the Neurl4→CP110 epistasis in Drosophila confirmed CP110 downregulation as the core ancestral function and extended it to germ cell biology.\",\n      \"evidence\": \"Drosophila loss-of-function genetics and double-mutant suppressor analysis with immunofluorescence\",\n      \"pmids\": [\"26116656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The germ plasm role appears separable from CP110 regulation and remains mechanistically undefined\",\n        \"Molecular link between CP110 control and PGC morphology not detailed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating direct NEURL4–p53 binding via NHR domains 3–4 revealed a non-degradative role: NEURL4 promotes p53 tetramerization and transcriptional output, expanding its function into tumor-suppressor signaling.\",\n      \"evidence\": \"Co-IP, domain mapping, luciferase reporter and clonogenic assays, knockdown/overexpression, single lab\",\n      \"pmids\": [\"28977907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of how NEURL4 binding favors p53 tetramers not resolved\",\n        \"Whether HERC2 ubiquitin activity contributes mechanistically unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placing NEURL4 within the neuronal cytoplasmic RNF8–UBC13–HERC2 network established its role in suppressing synapse formation in cerebellum.\",\n      \"evidence\": \"AP-MS, in vivo RNAi, conditional knockout, electrophysiology, and confocal imaging with genetic epistasis (KD phenocopy)\",\n      \"pmids\": [\"29097665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Synaptic substrate(s) ubiquitylated by this network not identified\",\n        \"How a cytoplasmic ubiquitin signal limits bouton number mechanistically unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining a DNA-damage-responsive p53/HERC2/NEURL4/MDM2 complex showed how NEURL4-bound oligomeric p53 is modified and partitioned between HERC2 and the MDM2 promoter, linking the scaffold to the p53–MDM2 feedback loop.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, promoter reporter assays, Western blot, and RT-PCR after bleomycin treatment\",\n      \"pmids\": [\"31665549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct contribution of NEURL4 (versus HERC2) to MDM2 promoter regulation not separated\",\n        \"Kinetics of complex dissociation after DNA damage incompletely defined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying NEURL4 as the principal mitochondrial ADP-ribosyltransferase that poly-ADP-ribosylates mtLIG3 defined an enzymatic, organelle-specific function in mtDNA base excision repair, distinct from its scaffolding roles.\",\n      \"evidence\": \"In vitro ART activity assays on mitochondrial extracts, NEURL4 KO/KD, ADP-ribosylome mass spectrometry, and mtDNA integrity readout\",\n      \"pmids\": [\"35157000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Catalytic domain/residues mediating ART activity within NEURL4 not mapped\",\n        \"How NEURL4 enzymatic activity is regulated and coordinated with its centrosomal/nuclear roles unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NEURL4 partitions and coordinates its distinct enzymatic (mitochondrial ART) and scaffolding (centrosomal, p53, synaptic, trafficking) activities, and which domains confer each, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure of full-length human NEURL4 or its catalytic ART module\",\n        \"No unified model linking subcellular pools to specific functions\",\n        \"Regulation of NEURL4 by its own HERC2-mediated ubiquitylation across compartments unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"NEURL4–HERC2 complex\",\n      \"LRRK2–NEURL4–HERC2 complex\",\n      \"RNF8–UBC13–HERC2–NEURL4 network\",\n      \"p53/HERC2/NEURL4/MDM2 complex\"\n    ],\n    \"partners\": [\n      \"HERC2\",\n      \"CP110\",\n      \"TP53\",\n      \"MDM2\",\n      \"LRRK2\",\n      \"RNF8\",\n      \"ODF2\",\n      \"MAPK6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}