{"gene":"COMMD10","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2017,"finding":"FMNL2 targets COMMD10 for ubiquitin-mediated proteasome degradation; COMMD10 in turn binds the p65 NF-κB subunit and reduces its nuclear translocation, thereby suppressing NF-κB pathway activity and CRC invasion/metastasis.","method":"Co-IP, GST pull-down, in vitro ubiquitination assay, dual-luciferase reporter assay, nuclear protein extraction assay, western blot","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, pulldown, in vitro ubiquitination, reporter assay) in a single study establishing the FMNL2→COMMD10→p65 axis","pmids":["28817833"],"is_preprint":false},{"year":2022,"finding":"COMMD10 inhibits ubiquitin-mediated degradation of HIF1α (counteracted by Cu accumulation) and physically associates with HIF1α to block its nuclear translocation; loss of COMMD10 promotes HIF1α-driven transcription of ceruloplasmin (CP) and SLC7A11, suppressing ferroptosis and conferring radioresistance in HCC.","method":"Co-IP (COMMD10–HIF1α interaction), ubiquitination assay, western blot, immunostaining, glutathione/lipid peroxidation/MDA/Fe2+ assays, lentiviral overexpression/knockdown, in vivo mouse radiation models","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical and in vivo methods with mechanistic rescue experiments, single study but strongly controlled","pmids":["35101526"],"is_preprint":false},{"year":2018,"finding":"COMMD10 positively regulates ENaC activity; stable COMMD10 knockdown decreases ENaC current, increases Nedd4-2 protein levels, and impairs transferrin endocytosis and recycling, indicating COMMD10 controls ENaC through multiple trafficking pathways including counteraction of Nedd4-2-mediated ubiquitination.","method":"Stable shRNA knockdown in Fischer rat thyroid epithelia, Ussing chamber electrophysiology, transferrin recycling/endocytosis assay, western blot, Co-IP (ENaC–COMMD10 interaction)","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — clean KD with defined functional readout and interaction confirmed, but mechanistic pathway partially resolved","pmids":["29997525"],"is_preprint":false},{"year":2019,"finding":"COMMD10 in macrophages is required for phagolysosomal maturation during S. aureus infection; its deficiency impairs transcription factor EB (TFEB) activation, reduces lysosomal biogenesis, and diminishes expression of the CCC (COMMD/CCDC22/CCDC93) complex.","method":"COMMD10-deficient macrophage and Kupffer cell models (in vivo and in vitro), TFEB activity assay, lysosomal biogenesis markers, S. aureus bacterial clearance assay, western blot","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype and pathway placement (TFEB/lysosomal biogenesis, CCC complex), single study","pmids":["30959277"],"is_preprint":false},{"year":2018,"finding":"COMMD10 in myeloid Ly6Chi monocytes curbs canonical and non-canonical inflammasome activity; its myeloid-specific deficiency increases caspase-1 and caspase-11 activation, augments IL-1β production, and disrupts intestinal barrier function.","method":"Myeloid cell-specific conditional knockout mice, caspase-1/-11 activity assays, ELISA for cytokines, intestinal permeability assay, inducible monocyte ablation, DSS colitis model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific KO with defined pathway (inflammasome) and phenotypic readout, single study","pmids":["30487795"],"is_preprint":false},{"year":2021,"finding":"COMMD10 is required for homeostatic survival of Kupffer cells and other tissue-resident macrophages; its deficiency leads to impaired KC maintenance, continuous replacement by Ly6Chi monocytes, unleashed inflammasome activation, reduced type I interferon response, and aberrant monocyte differentiation in the injured liver.","method":"Conditional KO mice, flow cytometry, acetaminophen liver injury model, inflammasome activation assays, transcriptional profiling of monocyte fate","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific KO with multiple defined cellular phenotypes and pathway placements, single study","pmids":["34788631"],"is_preprint":false},{"year":2023,"finding":"COMMD10 is required for neural plate/neural crest development during embryogenesis; homozygous knockout mice arrest at E8.5 with markedly reduced expression of neural crest transcription factors (including Sox10) and neurogenesis-related growth factors.","method":"Commd10 knockout mouse model (Vav1-cre insertional KO), transcriptome analysis of E8.5 embryos","journal":"Journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with transcriptomic phenotype, but mechanistic pathway only partially defined","pmids":["36976102"],"is_preprint":false},{"year":2024,"finding":"COMMD10 inhibits DNA damage repair pathways in gastric cancer; knockdown of COMMD10 impairs DNA repair, intensifies DNA damage markers, and activates the ATM-p53 signaling cascade in vitro and in xenograft tumors.","method":"shRNA knockdown, western blot, immunofluorescence (γH2AX), xenograft mouse model, cisplatin-induced DNA damage assay","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, KD with phenotype but no direct biochemical mechanism for how COMMD10 interfaces with DNA repair machinery","pmids":["38871970"],"is_preprint":false},{"year":2025,"finding":"COMMD10 promotes angiogenesis suppression and bone formation through the Rap1 signaling pathway; COMMD10 knockdown in endothelial cells activates Rap1 signaling and enhances vascular formation, and double knockdown of RAP1B and COMMD10 attenuates this angiogenic effect.","method":"siRNA knockdown in endothelial cells, tube formation assay, RAP1B co-knockdown epistasis, gene/protein expression analysis","journal":"FASEB bioAdvances","confidence":"Low","confidence_rationale":"Tier 3 — single lab, genetic epistasis with limited mechanistic detail on how COMMD10 controls Rap1","pmids":["40496352"],"is_preprint":false},{"year":2024,"finding":"COMMD10 is required for regulated endosomal recycling of ENaC back to the plasma membrane; COMMD10 localizes to Rab5-, Rab7-, and Rab11-positive endosomes in a pattern similar to WASH and Arp2/3, and aldosterone downregulates while calcium upregulates COMMD10 protein levels.","method":"Knockdown studies, ENaC surface population assay, co-localization immunofluorescence with Rab5/Rab7/Rab11 markers and WASH/Arp2/3, western blot for aldosterone/calcium regulation","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, localization and KD data without full biochemical reconstitution","pmids":["bio_10.1101_2024.06.11.598390"],"is_preprint":true}],"current_model":"COMMD10 is a multifunctional scaffold/regulatory protein that (1) suppresses NF-κB signaling by binding p65 to prevent its nuclear translocation (while being itself degraded by FMNL2-driven ubiquitination), (2) modulates copper and iron homeostasis to control HIF1α stability and nuclear activity, thereby regulating ferroptosis, (3) facilitates phagolysosomal biogenesis via TFEB activation and the CCC complex in macrophages, (4) restrains inflammasome (caspase-1/-11) activity in Ly6Chi monocytes, (5) controls ENaC surface abundance through endosomal recycling pathways involving Rab5/7/11 and counteraction of Nedd4-2, and (6) is essential for neural crest development and tissue-resident macrophage homeostatic survival."},"narrative":{"teleology":[{"year":2017,"claim":"The first mechanistic link between COMMD10 and a signaling pathway was established: COMMD10 directly binds p65 and blocks its nuclear translocation, suppressing NF-κB activity, while FMNL2 negatively regulates this axis by driving COMMD10 ubiquitination and proteasomal degradation.","evidence":"Co-IP, GST pull-down, in vitro ubiquitination assay, dual-luciferase reporter, and nuclear fractionation in colorectal cancer cells","pmids":["28817833"],"confidence":"High","gaps":["The E3 ubiquitin ligase recruited by FMNL2 to ubiquitinate COMMD10 was not identified","Whether other COMMD family members compensate for COMMD10 loss in NF-κB regulation is unknown","Physiological relevance outside CRC cells was not tested"]},{"year":2018,"claim":"COMMD10 was placed at the intersection of endosomal trafficking and ion channel regulation: it positively regulates ENaC surface abundance by counteracting Nedd4-2-mediated ubiquitination and supporting transferrin endocytosis/recycling, and it restrains caspase-1/caspase-11 inflammasome activation in myeloid Ly6Cʰⁱ monocytes to maintain intestinal barrier integrity.","evidence":"Stable shRNA knockdown with Ussing chamber electrophysiology and transferrin recycling in epithelial cells; myeloid-specific conditional KO mice with caspase activity assays and DSS colitis model","pmids":["29997525","30487795"],"confidence":"Medium","gaps":["Direct physical interaction between COMMD10 and Nedd4-2 was not demonstrated","The molecular mechanism by which COMMD10 suppresses caspase-1/caspase-11 activation was not defined","Whether ENaC regulation and inflammasome restraint share a common COMMD10-dependent trafficking mechanism is unknown"]},{"year":2019,"claim":"COMMD10 was linked to the CCC complex and lysosomal biogenesis: in macrophages, COMMD10 deficiency impairs TFEB activation and reduces expression of CCC complex components, leading to defective phagolysosome maturation and impaired bacterial clearance.","evidence":"COMMD10-deficient macrophage and Kupffer cell models with TFEB activity assays, lysosomal markers, and S. aureus clearance","pmids":["30959277"],"confidence":"Medium","gaps":["Whether COMMD10 directly activates TFEB or acts indirectly through CCC-dependent endosomal signaling is unresolved","Biochemical reconstitution of the COMMD10–CCC interaction has not been performed","Contribution of individual CCC subunits to the phenotype was not dissected"]},{"year":2021,"claim":"The in vivo requirement for COMMD10 in tissue-resident macrophage homeostasis was established: its loss leads to Kupffer cell depletion, continuous monocyte replacement, aberrant inflammasome activation, and diminished type I interferon responses after liver injury.","evidence":"Conditional KO mice, flow cytometry, acetaminophen liver injury model, transcriptional profiling of monocyte differentiation","pmids":["34788631"],"confidence":"Medium","gaps":["The upstream signal that maintains COMMD10 expression in tissue-resident macrophages is unknown","Whether the KC survival defect is cell-intrinsic or secondary to inflammasome hyperactivation was not fully resolved","Relevance to tissue-resident macrophages outside the liver was only partially explored"]},{"year":2022,"claim":"A second major signaling axis was uncovered: COMMD10 physically associates with HIF1α, inhibits its ubiquitin-mediated degradation and nuclear translocation, and thereby controls HIF1α-driven transcription of ceruloplasmin and SLC7A11 to regulate ferroptosis and radioresistance in hepatocellular carcinoma.","evidence":"Co-IP, ubiquitination assay, glutathione/lipid peroxidation/Fe²⁺ assays, lentiviral overexpression/knockdown, in vivo mouse radiation models","pmids":["35101526"],"confidence":"High","gaps":["How copper accumulation mechanistically counteracts the COMMD10–HIF1α interaction is not defined at the structural level","Whether COMMD10 regulation of HIF1α extends to non-malignant hypoxic tissues is untested","The E3 ligase whose activity COMMD10 opposes on HIF1α was not identified"]},{"year":2023,"claim":"A developmental requirement was revealed: homozygous COMMD10 knockout causes embryonic lethality at E8.5 with severely reduced neural crest transcription factors including Sox10, establishing COMMD10 as essential for neural plate and neural crest development.","evidence":"Commd10 knockout mouse model with transcriptome analysis of E8.5 embryos","pmids":["36976102"],"confidence":"Medium","gaps":["The signaling pathway through which COMMD10 controls neural crest gene expression is unknown","Whether the embryonic lethality is caused specifically by neural crest failure or broader developmental arrest is unclear","Cell-autonomous versus non-cell-autonomous roles in neural crest progenitors were not distinguished"]},{"year":null,"claim":"Structural and biochemical details of COMMD10's integration into the CCC complex, the identity of E3 ligases it opposes on HIF1α and ENaC pathways, and the mechanism linking COMMD10 to neural crest transcription factor expression remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of COMMD10 alone or in complex","The direct enzymatic or adaptor mechanism by which COMMD10 opposes ubiquitination of its targets has not been reconstituted","Integration of the NF-κB, HIF1α, inflammasome, and trafficking functions into a unified molecular model is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]}],"complexes":["CCC complex (COMMD/CCDC22/CCDC93)"],"partners":["RELA","FMNL2","HIF1A","NEDD4L","TFEB"],"other_free_text":[]},"mechanistic_narrative":"COMMD10 is a scaffold/regulatory protein that modulates NF-κB signaling, endosomal trafficking, inflammasome activity, and HIF1α stability across diverse cell types. COMMD10 binds the NF-κB subunit p65 and prevents its nuclear translocation, thereby suppressing NF-κB-driven transcription; this function is negatively regulated by FMNL2, which targets COMMD10 for ubiquitin–proteasome degradation [PMID:28817833]. In hepatocellular carcinoma cells, COMMD10 physically associates with HIF1α to inhibit its ubiquitin-mediated degradation and nuclear entry, and loss of COMMD10 upregulates HIF1α-driven ceruloplasmin and SLC7A11 transcription, suppressing ferroptosis and promoting radioresistance [PMID:35101526]. In myeloid cells, COMMD10 restrains caspase-1/caspase-11 inflammasome activation in Ly6Cʰⁱ monocytes, promotes TFEB-dependent phagolysosomal biogenesis through the CCC complex in macrophages, and is essential for the homeostatic survival of tissue-resident Kupffer cells [PMID:30487795, PMID:30959277, PMID:34788631]."},"prefetch_data":{"uniprot":{"accession":"Q9Y6G5","full_name":"COMM domain-containing protein 10","aliases":[],"length_aa":202,"mass_kda":23.0,"function":"Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex (PubMed:37172566, PubMed:38459129). May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). May down-regulate activation of NF-kappa-B (PubMed:15799966)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y6G5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COMMD10","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC22","stoichiometry":10.0},{"gene":"CCDC93","stoichiometry":10.0},{"gene":"COMMD1","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"COMMD2","stoichiometry":0.2},{"gene":"COMMD4","stoichiometry":0.2},{"gene":"RAC1","stoichiometry":0.2},{"gene":"RHOA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COMMD10","total_profiled":1310},"omim":[{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"612299","title":"COMM DOMAIN-CONTAINING PROTEIN 9; COMMD9","url":"https://www.omim.org/entry/612299"},{"mim_id":"607238","title":"COMM DOMAIN-CONTAINING PROTEIN 1; COMMD1","url":"https://www.omim.org/entry/607238"},{"mim_id":"300859","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 22; CCDC22","url":"https://www.omim.org/entry/300859"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COMMD10"},"hgnc":{"alias_symbol":["PTD002"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6G5","domains":[{"cath_id":"-","chopping":"14-127","consensus_level":"high","plddt":89.5077,"start":14,"end":127},{"cath_id":"-","chopping":"133-201","consensus_level":"high","plddt":82.7239,"start":133,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6G5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6G5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6G5-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COMMD10","jax_strain_url":"https://www.jax.org/strain/search?query=COMMD10"},"sequence":{"accession":"Q9Y6G5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6G5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6G5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6G5"}},"corpus_meta":[{"pmid":"35101526","id":"PMC_35101526","title":"COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.","date":"2022","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35101526","citation_count":206,"is_preprint":false},{"pmid":"28817833","id":"PMC_28817833","title":"FMNL2 destabilises COMMD10 to activate NF-κB pathway in invasion and metastasis of colorectal cancer.","date":"2017","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28817833","citation_count":34,"is_preprint":false},{"pmid":"30959277","id":"PMC_30959277","title":"COMMD10-Guided Phagolysosomal Maturation Promotes Clearance of Staphylococcus aureus in Macrophages.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/30959277","citation_count":18,"is_preprint":false},{"pmid":"30487795","id":"PMC_30487795","title":"Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30487795","citation_count":16,"is_preprint":false},{"pmid":"34788631","id":"PMC_34788631","title":"COMMD10 is critical for Kupffer cell survival and controls Ly6Chi monocyte differentiation and inflammation in the injured liver.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34788631","citation_count":14,"is_preprint":false},{"pmid":"29997525","id":"PMC_29997525","title":"Epithelial Na+ Channel: Reciprocal Control by COMMD10 and Nedd4-2.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29997525","citation_count":11,"is_preprint":false},{"pmid":"40496352","id":"PMC_40496352","title":"COMMD10 Regulates Angiogenesis and Bone Formation via Rap1 Signaling Pathway.","date":"2025","source":"FASEB bioAdvances","url":"https://pubmed.ncbi.nlm.nih.gov/40496352","citation_count":3,"is_preprint":false},{"pmid":"36976102","id":"PMC_36976102","title":"COMMD10 Is Essential for Neural Plate Development during Embryogenesis.","date":"2023","source":"Journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36976102","citation_count":2,"is_preprint":false},{"pmid":"38871970","id":"PMC_38871970","title":"COMMD10 inhibited DNA damage to promote the progression of gastric cancer.","date":"2024","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38871970","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.03.25334985","title":"Early Prediction of Gestational Diabetes Using Integrated Cell-free DNA Features and Omics-derived Genetic Scores","date":"2025-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.03.25334985","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.11.598390","title":"COMMD10 Regulates Endosomal Recycling of Epithelial Sodium Channel (ENaC)","date":"2024-06-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.11.598390","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7291,"output_tokens":2552,"usd":0.030076},"stage2":{"model":"claude-opus-4-6","input_tokens":5919,"output_tokens":2422,"usd":0.135217},"total_usd":0.165293,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"FMNL2 targets COMMD10 for ubiquitin-mediated proteasome degradation; COMMD10 in turn binds the p65 NF-κB subunit and reduces its nuclear translocation, thereby suppressing NF-κB pathway activity and CRC invasion/metastasis.\",\n      \"method\": \"Co-IP, GST pull-down, in vitro ubiquitination assay, dual-luciferase reporter assay, nuclear protein extraction assay, western blot\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, pulldown, in vitro ubiquitination, reporter assay) in a single study establishing the FMNL2→COMMD10→p65 axis\",\n      \"pmids\": [\"28817833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"COMMD10 inhibits ubiquitin-mediated degradation of HIF1α (counteracted by Cu accumulation) and physically associates with HIF1α to block its nuclear translocation; loss of COMMD10 promotes HIF1α-driven transcription of ceruloplasmin (CP) and SLC7A11, suppressing ferroptosis and conferring radioresistance in HCC.\",\n      \"method\": \"Co-IP (COMMD10–HIF1α interaction), ubiquitination assay, western blot, immunostaining, glutathione/lipid peroxidation/MDA/Fe2+ assays, lentiviral overexpression/knockdown, in vivo mouse radiation models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical and in vivo methods with mechanistic rescue experiments, single study but strongly controlled\",\n      \"pmids\": [\"35101526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COMMD10 positively regulates ENaC activity; stable COMMD10 knockdown decreases ENaC current, increases Nedd4-2 protein levels, and impairs transferrin endocytosis and recycling, indicating COMMD10 controls ENaC through multiple trafficking pathways including counteraction of Nedd4-2-mediated ubiquitination.\",\n      \"method\": \"Stable shRNA knockdown in Fischer rat thyroid epithelia, Ussing chamber electrophysiology, transferrin recycling/endocytosis assay, western blot, Co-IP (ENaC–COMMD10 interaction)\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — clean KD with defined functional readout and interaction confirmed, but mechanistic pathway partially resolved\",\n      \"pmids\": [\"29997525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"COMMD10 in macrophages is required for phagolysosomal maturation during S. aureus infection; its deficiency impairs transcription factor EB (TFEB) activation, reduces lysosomal biogenesis, and diminishes expression of the CCC (COMMD/CCDC22/CCDC93) complex.\",\n      \"method\": \"COMMD10-deficient macrophage and Kupffer cell models (in vivo and in vitro), TFEB activity assay, lysosomal biogenesis markers, S. aureus bacterial clearance assay, western blot\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype and pathway placement (TFEB/lysosomal biogenesis, CCC complex), single study\",\n      \"pmids\": [\"30959277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COMMD10 in myeloid Ly6Chi monocytes curbs canonical and non-canonical inflammasome activity; its myeloid-specific deficiency increases caspase-1 and caspase-11 activation, augments IL-1β production, and disrupts intestinal barrier function.\",\n      \"method\": \"Myeloid cell-specific conditional knockout mice, caspase-1/-11 activity assays, ELISA for cytokines, intestinal permeability assay, inducible monocyte ablation, DSS colitis model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with defined pathway (inflammasome) and phenotypic readout, single study\",\n      \"pmids\": [\"30487795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COMMD10 is required for homeostatic survival of Kupffer cells and other tissue-resident macrophages; its deficiency leads to impaired KC maintenance, continuous replacement by Ly6Chi monocytes, unleashed inflammasome activation, reduced type I interferon response, and aberrant monocyte differentiation in the injured liver.\",\n      \"method\": \"Conditional KO mice, flow cytometry, acetaminophen liver injury model, inflammasome activation assays, transcriptional profiling of monocyte fate\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with multiple defined cellular phenotypes and pathway placements, single study\",\n      \"pmids\": [\"34788631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COMMD10 is required for neural plate/neural crest development during embryogenesis; homozygous knockout mice arrest at E8.5 with markedly reduced expression of neural crest transcription factors (including Sox10) and neurogenesis-related growth factors.\",\n      \"method\": \"Commd10 knockout mouse model (Vav1-cre insertional KO), transcriptome analysis of E8.5 embryos\",\n      \"journal\": \"Journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with transcriptomic phenotype, but mechanistic pathway only partially defined\",\n      \"pmids\": [\"36976102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COMMD10 inhibits DNA damage repair pathways in gastric cancer; knockdown of COMMD10 impairs DNA repair, intensifies DNA damage markers, and activates the ATM-p53 signaling cascade in vitro and in xenograft tumors.\",\n      \"method\": \"shRNA knockdown, western blot, immunofluorescence (γH2AX), xenograft mouse model, cisplatin-induced DNA damage assay\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with phenotype but no direct biochemical mechanism for how COMMD10 interfaces with DNA repair machinery\",\n      \"pmids\": [\"38871970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COMMD10 promotes angiogenesis suppression and bone formation through the Rap1 signaling pathway; COMMD10 knockdown in endothelial cells activates Rap1 signaling and enhances vascular formation, and double knockdown of RAP1B and COMMD10 attenuates this angiogenic effect.\",\n      \"method\": \"siRNA knockdown in endothelial cells, tube formation assay, RAP1B co-knockdown epistasis, gene/protein expression analysis\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, genetic epistasis with limited mechanistic detail on how COMMD10 controls Rap1\",\n      \"pmids\": [\"40496352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COMMD10 is required for regulated endosomal recycling of ENaC back to the plasma membrane; COMMD10 localizes to Rab5-, Rab7-, and Rab11-positive endosomes in a pattern similar to WASH and Arp2/3, and aldosterone downregulates while calcium upregulates COMMD10 protein levels.\",\n      \"method\": \"Knockdown studies, ENaC surface population assay, co-localization immunofluorescence with Rab5/Rab7/Rab11 markers and WASH/Arp2/3, western blot for aldosterone/calcium regulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, localization and KD data without full biochemical reconstitution\",\n      \"pmids\": [\"bio_10.1101_2024.06.11.598390\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"COMMD10 is a multifunctional scaffold/regulatory protein that (1) suppresses NF-κB signaling by binding p65 to prevent its nuclear translocation (while being itself degraded by FMNL2-driven ubiquitination), (2) modulates copper and iron homeostasis to control HIF1α stability and nuclear activity, thereby regulating ferroptosis, (3) facilitates phagolysosomal biogenesis via TFEB activation and the CCC complex in macrophages, (4) restrains inflammasome (caspase-1/-11) activity in Ly6Chi monocytes, (5) controls ENaC surface abundance through endosomal recycling pathways involving Rab5/7/11 and counteraction of Nedd4-2, and (6) is essential for neural crest development and tissue-resident macrophage homeostatic survival.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COMMD10 is a scaffold/regulatory protein that modulates NF-κB signaling, endosomal trafficking, inflammasome activity, and HIF1α stability across diverse cell types. COMMD10 binds the NF-κB subunit p65 and prevents its nuclear translocation, thereby suppressing NF-κB-driven transcription; this function is negatively regulated by FMNL2, which targets COMMD10 for ubiquitin–proteasome degradation [PMID:28817833]. In hepatocellular carcinoma cells, COMMD10 physically associates with HIF1α to inhibit its ubiquitin-mediated degradation and nuclear entry, and loss of COMMD10 upregulates HIF1α-driven ceruloplasmin and SLC7A11 transcription, suppressing ferroptosis and promoting radioresistance [PMID:35101526]. In myeloid cells, COMMD10 restrains caspase-1/caspase-11 inflammasome activation in Ly6Cʰⁱ monocytes, promotes TFEB-dependent phagolysosomal biogenesis through the CCC complex in macrophages, and is essential for the homeostatic survival of tissue-resident Kupffer cells [PMID:30487795, PMID:30959277, PMID:34788631].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"The first mechanistic link between COMMD10 and a signaling pathway was established: COMMD10 directly binds p65 and blocks its nuclear translocation, suppressing NF-κB activity, while FMNL2 negatively regulates this axis by driving COMMD10 ubiquitination and proteasomal degradation.\",\n      \"evidence\": \"Co-IP, GST pull-down, in vitro ubiquitination assay, dual-luciferase reporter, and nuclear fractionation in colorectal cancer cells\",\n      \"pmids\": [\"28817833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The E3 ubiquitin ligase recruited by FMNL2 to ubiquitinate COMMD10 was not identified\",\n        \"Whether other COMMD family members compensate for COMMD10 loss in NF-κB regulation is unknown\",\n        \"Physiological relevance outside CRC cells was not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"COMMD10 was placed at the intersection of endosomal trafficking and ion channel regulation: it positively regulates ENaC surface abundance by counteracting Nedd4-2-mediated ubiquitination and supporting transferrin endocytosis/recycling, and it restrains caspase-1/caspase-11 inflammasome activation in myeloid Ly6Cʰⁱ monocytes to maintain intestinal barrier integrity.\",\n      \"evidence\": \"Stable shRNA knockdown with Ussing chamber electrophysiology and transferrin recycling in epithelial cells; myeloid-specific conditional KO mice with caspase activity assays and DSS colitis model\",\n      \"pmids\": [\"29997525\", \"30487795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between COMMD10 and Nedd4-2 was not demonstrated\",\n        \"The molecular mechanism by which COMMD10 suppresses caspase-1/caspase-11 activation was not defined\",\n        \"Whether ENaC regulation and inflammasome restraint share a common COMMD10-dependent trafficking mechanism is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"COMMD10 was linked to the CCC complex and lysosomal biogenesis: in macrophages, COMMD10 deficiency impairs TFEB activation and reduces expression of CCC complex components, leading to defective phagolysosome maturation and impaired bacterial clearance.\",\n      \"evidence\": \"COMMD10-deficient macrophage and Kupffer cell models with TFEB activity assays, lysosomal markers, and S. aureus clearance\",\n      \"pmids\": [\"30959277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether COMMD10 directly activates TFEB or acts indirectly through CCC-dependent endosomal signaling is unresolved\",\n        \"Biochemical reconstitution of the COMMD10–CCC interaction has not been performed\",\n        \"Contribution of individual CCC subunits to the phenotype was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The in vivo requirement for COMMD10 in tissue-resident macrophage homeostasis was established: its loss leads to Kupffer cell depletion, continuous monocyte replacement, aberrant inflammasome activation, and diminished type I interferon responses after liver injury.\",\n      \"evidence\": \"Conditional KO mice, flow cytometry, acetaminophen liver injury model, transcriptional profiling of monocyte differentiation\",\n      \"pmids\": [\"34788631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The upstream signal that maintains COMMD10 expression in tissue-resident macrophages is unknown\",\n        \"Whether the KC survival defect is cell-intrinsic or secondary to inflammasome hyperactivation was not fully resolved\",\n        \"Relevance to tissue-resident macrophages outside the liver was only partially explored\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A second major signaling axis was uncovered: COMMD10 physically associates with HIF1α, inhibits its ubiquitin-mediated degradation and nuclear translocation, and thereby controls HIF1α-driven transcription of ceruloplasmin and SLC7A11 to regulate ferroptosis and radioresistance in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, glutathione/lipid peroxidation/Fe²⁺ assays, lentiviral overexpression/knockdown, in vivo mouse radiation models\",\n      \"pmids\": [\"35101526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How copper accumulation mechanistically counteracts the COMMD10–HIF1α interaction is not defined at the structural level\",\n        \"Whether COMMD10 regulation of HIF1α extends to non-malignant hypoxic tissues is untested\",\n        \"The E3 ligase whose activity COMMD10 opposes on HIF1α was not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A developmental requirement was revealed: homozygous COMMD10 knockout causes embryonic lethality at E8.5 with severely reduced neural crest transcription factors including Sox10, establishing COMMD10 as essential for neural plate and neural crest development.\",\n      \"evidence\": \"Commd10 knockout mouse model with transcriptome analysis of E8.5 embryos\",\n      \"pmids\": [\"36976102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The signaling pathway through which COMMD10 controls neural crest gene expression is unknown\",\n        \"Whether the embryonic lethality is caused specifically by neural crest failure or broader developmental arrest is unclear\",\n        \"Cell-autonomous versus non-cell-autonomous roles in neural crest progenitors were not distinguished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Structural and biochemical details of COMMD10's integration into the CCC complex, the identity of E3 ligases it opposes on HIF1α and ENaC pathways, and the mechanism linking COMMD10 to neural crest transcription factor expression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of COMMD10 alone or in complex\",\n        \"The direct enzymatic or adaptor mechanism by which COMMD10 opposes ubiquitination of its targets has not been reconstituted\",\n        \"Integration of the NF-κB, HIF1α, inflammasome, and trafficking functions into a unified molecular model is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"CCC complex (COMMD/CCDC22/CCDC93)\"\n    ],\n    \"partners\": [\n      \"RELA\",\n      \"FMNL2\",\n      \"HIF1A\",\n      \"NEDD4L\",\n      \"TFEB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}