{"gene":"COMMD10","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2022,"finding":"COMMD10 interacts with HIF1α and promotes its ubiquitin-mediated proteasomal degradation. Ionizing radiation reduces COMMD10 expression, leading to Cu accumulation that inhibits HIF1α ubiquitin degradation and impairs COMMD10's direct interaction with HIF1α, thereby promoting HIF1α nuclear translocation and transcription of ceruloplasmin (CP) and SLC7A11, which together inhibit ferroptosis in HCC cells.","method":"Western blot, real-time PCR, immunostaining, radiation clonogenic assay, in vivo lentivirus-modified mouse models, glutathione/lipid peroxidation/MDA/Fe2+ assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods in a single lab; direct interaction and ubiquitin degradation mechanistic claims supported but no in vitro reconstitution or mutagenesis of the COMMD10–HIF1α interaction","pmids":["35101526"],"is_preprint":false},{"year":2017,"finding":"FMNL2 physically interacts with COMMD10 (confirmed by Co-IP and GST pull-down) and targets it for ubiquitin-mediated proteasomal degradation. COMMD10 in turn binds the p65 NF-κB subunit and reduces its nuclear translocation, thereby inactivating the NF-κB pathway and suppressing colorectal cancer invasion and metastasis.","method":"Co-IP, GST pull-down, in vitro ubiquitination assay, dual-luciferase reporter assay, nuclear protein extraction, western blot, immunofluorescence, animal models","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, GST pull-down, in vitro ubiquitination assay, and functional reporter assays, multiple orthogonal methods in single study establishing FMNL2→COMMD10→p65 axis","pmids":["28817833"],"is_preprint":false},{"year":2019,"finding":"COMMD10 is required for phagolysosomal maturation in macrophages during S. aureus infection. COMMD10-deficient macrophages exhibit impaired activation of transcription factor EB (TFEB), reduced lysosomal biogenesis, attenuated phagolysosomal maturation and function, and reduced expression of the CCC (COMMD/CCDC22/CCDC93) complex, which is linked to phagolysosomal maturation.","method":"Genetic knockout (COMMD10-deficient macrophages and Kupffer cells), in vivo S. aureus infection model, functional phagolysosomal maturation assays, TFEB activity assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and pathway placement (TFEB/lysosomal biogenesis), single lab, in vivo and in vitro","pmids":["30959277"],"is_preprint":false},{"year":2018,"finding":"COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes. COMMD10 deficiency in myeloid cells (but not tissue-resident macrophages) increases caspase-1 and caspase-11 activation and augments IL-1β production, demonstrating a cell-type-specific role for COMMD10 as a negative regulator of inflammasome signaling.","method":"Conditional myeloid-specific knockout, LPS-induced systemic inflammation model, DSS-induced colitis model, caspase-1/11 activation assays, cytokine measurements, inducible Ly6Chi monocyte ablation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular and molecular phenotype (caspase activation, IL-1β), multiple in vivo models, single lab","pmids":["30487795"],"is_preprint":false},{"year":2021,"finding":"COMMD10 is indispensable for the homeostatic survival of Kupffer cells and other tissue-resident macrophages; its deficiency leads to continuous replacement by Ly6Chi monocytes. In Ly6Chi monocytes, COMMD10 deficiency unleashes inflammasome activation, reduces type I interferon response, and skews differentiation toward 'neutrophil-like' and lipid-associated macrophage fates during liver injury.","method":"Conditional knockout mouse models, acetaminophen-induced liver injury, inflammasome activation assays, type I IFN response assays, fate-mapping/differentiation analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple defined phenotypes and pathway placements, single lab, in vivo","pmids":["34788631"],"is_preprint":false},{"year":2018,"finding":"COMMD10 interacts with ENaC (epithelial Na+ channel) and positively regulates ENaC current in epithelial cells. Stable COMMD10 knockdown decreases ENaC current associated with increased Nedd4-2 protein (a negative regulator of ENaC), and causes defects in both endocytosis and recycling of transferrin, indicating COMMD10 modulates ENaC through multiple trafficking pathways.","method":"Co-immunoprecipitation (interaction confirmation), stable shRNA knockdown in Fischer rat thyroid epithelia, electrophysiology (ENaC current), transferrin endocytosis/recycling assay, western blot","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — confirmed interaction by Co-IP, functional KD with electrophysiology readout, trafficking assay; partial rescue only, single lab","pmids":["29997525"],"is_preprint":false},{"year":2025,"finding":"COMMD10 knockdown in endothelial cells enhances vascular formation (angiogenesis) and promotes bone formation by inducing secretion of pro-osteogenic factors. This effect is mediated through activation of the Rap1 signaling pathway; double knockdown of RAP1B and COMMD10 attenuates the angiogenic ability of endothelial cells.","method":"COMMD10 knockdown in endothelial cells, angiogenesis assays, gene/protein expression analysis, double knockdown epistasis (RAP1B + COMMD10)","journal":"FASEB bioAdvances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single KD approach with epistasis; no reconstitution or direct binding assay linking COMMD10 to Rap1 pathway components","pmids":["40496352"],"is_preprint":false},{"year":2023,"finding":"COMMD10 is required for neural plate and neural crest development during embryogenesis; Commd10-deficient mouse embryos arrest by E8.5 with markedly reduced expression of neural crest transcription factors (including Sox10) and neurogenesis-related cytokines/growth factors, alongside upregulation of tissue remodeling and regression genes.","method":"Commd10 knockout mice (Vav1-cre–mediated functional KO in homozygotes), embryo phenotyping, transcriptome analysis","journal":"Journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with embryonic lethality phenotype and transcriptome characterization; mechanistic pathway placement is descriptive/transcriptomic rather than biochemical","pmids":["36976102"],"is_preprint":false},{"year":2024,"finding":"COMMD10 promotes DNA damage repair and maintains genomic stability in gastric cancer cells. Knockdown of COMMD10 impairs DNA damage repair, intensifies DNA damage, and activates the ATM-p53 signaling pathway both in vitro and in xenograft tumors; restoration of COMMD10 suppresses DNA damage and ATM-p53 activation.","method":"COMMD10 knockdown and restoration in GC cell lines, in vivo xenograft tumor experiments, western blot, immunofluorescence for DNA damage markers, ATM-p53 pathway activation assays","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD/rescue approach with pathway activation assay; no direct biochemical mechanism linking COMMD10 to DNA repair machinery","pmids":["38871970"],"is_preprint":false}],"current_model":"COMMD10 is a multifunctional regulator that (1) suppresses NF-κB signaling by binding p65 and reducing its nuclear translocation (and is itself degraded by FMNL2-mediated ubiquitination), (2) controls Cu/Fe homeostasis and HIF1α stability to modulate ferroptosis and radiosensitivity, (3) promotes phagolysosomal maturation and lysosomal biogenesis (via TFEB) in macrophages for bacterial clearance, (4) restrains inflammasome (caspase-1/11) activation in Ly6Chi monocytes, (5) supports tissue-resident macrophage survival, (6) positively regulates ENaC trafficking and current in epithelial cells by antagonizing Nedd4-2, (7) is essential for embryonic neural crest development, and (8) maintains genomic stability by supporting DNA damage repair through the ATM-p53 pathway."},"narrative":{"mechanistic_narrative":"COMMD10 is a member of the COMMD/CCC complex that acts as a regulator of protein trafficking, metal homeostasis, and inflammatory signaling across epithelial and myeloid cell types [PMID:30959277, PMID:29997525]. It functions as a negative regulator of NF-κB signaling by binding the p65 subunit and reducing its nuclear translocation; this activity is itself controlled by FMNL2, which physically interacts with COMMD10 and targets it for ubiquitin-mediated proteasomal degradation [PMID:28817833]. COMMD10 promotes the ubiquitin-dependent proteasomal degradation of HIF1α and constrains copper accumulation, and loss of this activity (for example following ionizing radiation) stabilizes HIF1α and drives transcription of ceruloplasmin and SLC7A11 to suppress ferroptosis [PMID:35101526]. In macrophages, COMMD10 supports TFEB-driven lysosomal biogenesis and phagolysosomal maturation required for bacterial clearance, sustains tissue-resident macrophage survival, and restrains canonical and non-canonical inflammasome (caspase-1/11) activation in Ly6Chi monocytes [PMID:30959277, PMID:30487795, PMID:34788631]. In epithelial cells COMMD10 binds the epithelial Na+ channel (ENaC) and positively regulates its current by antagonizing Nedd4-2 while also influencing endocytic trafficking [PMID:29997525]. COMMD10 is essential for neural plate and neural crest development, with knockout embryos arresting by E8.5 and showing loss of neural crest transcription factors including Sox10 [PMID:36976102].","teleology":[{"year":2017,"claim":"Established COMMD10 as a node controlling its own stability and NF-κB output, answering how an upstream factor (FMNL2) tunes inflammatory and metastatic signaling.","evidence":"Reciprocal Co-IP, GST pull-down, in vitro ubiquitination, and dual-luciferase reporter assays in colorectal cancer cells","pmids":["28817833"],"confidence":"High","gaps":["Domain/residues mediating COMMD10–p65 binding not mapped","Whether FMNL2 is the ubiquitin ligase or a recruiter not resolved"]},{"year":2018,"claim":"Defined a cell-type-specific role for COMMD10 as a brake on inflammasome activation, distinguishing its function in Ly6Chi monocytes from tissue-resident macrophages.","evidence":"Myeloid-specific conditional knockout with LPS and DSS colitis models and caspase-1/11 activation assays","pmids":["30487795"],"confidence":"Medium","gaps":["Molecular mechanism by which COMMD10 suppresses caspase activation unknown","Direct inflammasome component interactions not shown"]},{"year":2018,"claim":"Showed COMMD10 physically interacts with ENaC and positively regulates channel current, linking it to Nedd4-2 antagonism and endocytic trafficking.","evidence":"Co-IP, stable shRNA knockdown in Fischer rat thyroid epithelia, electrophysiology, and transferrin trafficking assays","pmids":["29997525"],"confidence":"Medium","gaps":["Only partial functional rescue","Mechanistic basis of Nedd4-2 antagonism not defined"]},{"year":2019,"claim":"Placed COMMD10 in phagolysosomal maturation via TFEB-driven lysosomal biogenesis and the CCC complex during bacterial infection.","evidence":"COMMD10-deficient macrophages/Kupffer cells, in vivo S. aureus infection, and TFEB activity assays","pmids":["30959277"],"confidence":"Medium","gaps":["Direct molecular link from COMMD10 to TFEB activation not established","Single lab"]},{"year":2021,"claim":"Demonstrated COMMD10 is required for homeostatic survival of tissue-resident macrophages and shapes monocyte fate during liver injury.","evidence":"Conditional knockout mice, acetaminophen liver injury, inflammasome and type I IFN assays, fate-mapping","pmids":["34788631"],"confidence":"Medium","gaps":["Mechanism of survival dependence not biochemically defined","Causal ordering between inflammasome derepression and fate skewing unclear"]},{"year":2022,"claim":"Identified COMMD10 as a regulator of HIF1α stability and copper homeostasis that controls ferroptosis and radiosensitivity in hepatocellular carcinoma.","evidence":"Western blot, qPCR, clonogenic radiation assays, lentivirus mouse models, and lipid peroxidation/Fe2+/Cu assays","pmids":["35101526"],"confidence":"Medium","gaps":["No in vitro reconstitution or mutagenesis of the COMMD10–HIF1α interaction","Ubiquitin ligase involved not identified"]},{"year":2023,"claim":"Established an essential developmental requirement for COMMD10 in neural plate and neural crest formation.","evidence":"Commd10 knockout mice with embryo phenotyping and transcriptome analysis","pmids":["36976102"],"confidence":"Medium","gaps":["Mechanistic placement is transcriptomic/descriptive rather than biochemical","Specific COMMD10 targets driving neural crest gene loss unknown"]},{"year":2024,"claim":"Linked COMMD10 to maintenance of genomic stability through suppression of ATM-p53 signaling and support of DNA damage repair.","evidence":"Knockdown/restoration in gastric cancer cells, xenografts, and DNA damage marker/ATM-p53 assays","pmids":["38871970"],"confidence":"Low","gaps":["No direct biochemical link to DNA repair machinery","Single lab, KD/rescue only"]},{"year":2025,"claim":"Implicated COMMD10 as a restraint on endothelial angiogenesis and osteogenic crosstalk via the Rap1 pathway.","evidence":"Endothelial knockdown, angiogenesis assays, and RAP1B/COMMD10 double-knockdown epistasis","pmids":["40496352"],"confidence":"Low","gaps":["No direct binding assay linking COMMD10 to Rap1 components","Single KD approach without reconstitution"]},{"year":null,"claim":"How COMMD10's diverse roles (NF-κB, HIF1α/copper, lysosomal/TFEB, ENaC trafficking, development, DNA repair) converge on a unifying biochemical activity remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of COMMD10","Whether all functions depend on the CCC complex unknown","Direct enzymatic or adaptor activity not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,0]}],"complexes":["CCC (COMMD/CCDC22/CCDC93) complex"],"partners":["FMNL2","RELA","HIF1A","ENAC","NEDD4L"],"other_free_text":[]}},"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":210,"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":19,"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":3,"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7572,"output_tokens":2650,"usd":0.031233,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9941,"output_tokens":3001,"usd":0.062365,"stage2_stop_reason":"end_turn"},"total_usd":0.093598,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"COMMD10 interacts with HIF1α and promotes its ubiquitin-mediated proteasomal degradation. Ionizing radiation reduces COMMD10 expression, leading to Cu accumulation that inhibits HIF1α ubiquitin degradation and impairs COMMD10's direct interaction with HIF1α, thereby promoting HIF1α nuclear translocation and transcription of ceruloplasmin (CP) and SLC7A11, which together inhibit ferroptosis in HCC cells.\",\n      \"method\": \"Western blot, real-time PCR, immunostaining, radiation clonogenic assay, in vivo lentivirus-modified mouse models, glutathione/lipid peroxidation/MDA/Fe2+ assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods in a single lab; direct interaction and ubiquitin degradation mechanistic claims supported but no in vitro reconstitution or mutagenesis of the COMMD10–HIF1α interaction\",\n      \"pmids\": [\"35101526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FMNL2 physically interacts with COMMD10 (confirmed by Co-IP and GST pull-down) and targets it for ubiquitin-mediated proteasomal degradation. COMMD10 in turn binds the p65 NF-κB subunit and reduces its nuclear translocation, thereby inactivating the NF-κB pathway and suppressing colorectal cancer invasion and metastasis.\",\n      \"method\": \"Co-IP, GST pull-down, in vitro ubiquitination assay, dual-luciferase reporter assay, nuclear protein extraction, western blot, immunofluorescence, animal models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, GST pull-down, in vitro ubiquitination assay, and functional reporter assays, multiple orthogonal methods in single study establishing FMNL2→COMMD10→p65 axis\",\n      \"pmids\": [\"28817833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"COMMD10 is required for phagolysosomal maturation in macrophages during S. aureus infection. COMMD10-deficient macrophages exhibit impaired activation of transcription factor EB (TFEB), reduced lysosomal biogenesis, attenuated phagolysosomal maturation and function, and reduced expression of the CCC (COMMD/CCDC22/CCDC93) complex, which is linked to phagolysosomal maturation.\",\n      \"method\": \"Genetic knockout (COMMD10-deficient macrophages and Kupffer cells), in vivo S. aureus infection model, functional phagolysosomal maturation assays, TFEB activity assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and pathway placement (TFEB/lysosomal biogenesis), single lab, in vivo and in vitro\",\n      \"pmids\": [\"30959277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes. COMMD10 deficiency in myeloid cells (but not tissue-resident macrophages) increases caspase-1 and caspase-11 activation and augments IL-1β production, demonstrating a cell-type-specific role for COMMD10 as a negative regulator of inflammasome signaling.\",\n      \"method\": \"Conditional myeloid-specific knockout, LPS-induced systemic inflammation model, DSS-induced colitis model, caspase-1/11 activation assays, cytokine measurements, inducible Ly6Chi monocyte ablation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular and molecular phenotype (caspase activation, IL-1β), multiple in vivo models, single lab\",\n      \"pmids\": [\"30487795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COMMD10 is indispensable for the homeostatic survival of Kupffer cells and other tissue-resident macrophages; its deficiency leads to continuous replacement by Ly6Chi monocytes. In Ly6Chi monocytes, COMMD10 deficiency unleashes inflammasome activation, reduces type I interferon response, and skews differentiation toward 'neutrophil-like' and lipid-associated macrophage fates during liver injury.\",\n      \"method\": \"Conditional knockout mouse models, acetaminophen-induced liver injury, inflammasome activation assays, type I IFN response assays, fate-mapping/differentiation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple defined phenotypes and pathway placements, single lab, in vivo\",\n      \"pmids\": [\"34788631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COMMD10 interacts with ENaC (epithelial Na+ channel) and positively regulates ENaC current in epithelial cells. Stable COMMD10 knockdown decreases ENaC current associated with increased Nedd4-2 protein (a negative regulator of ENaC), and causes defects in both endocytosis and recycling of transferrin, indicating COMMD10 modulates ENaC through multiple trafficking pathways.\",\n      \"method\": \"Co-immunoprecipitation (interaction confirmation), stable shRNA knockdown in Fischer rat thyroid epithelia, electrophysiology (ENaC current), transferrin endocytosis/recycling assay, western blot\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — confirmed interaction by Co-IP, functional KD with electrophysiology readout, trafficking assay; partial rescue only, single lab\",\n      \"pmids\": [\"29997525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COMMD10 knockdown in endothelial cells enhances vascular formation (angiogenesis) and promotes bone formation by inducing secretion of pro-osteogenic factors. This effect is mediated through activation of the Rap1 signaling pathway; double knockdown of RAP1B and COMMD10 attenuates the angiogenic ability of endothelial cells.\",\n      \"method\": \"COMMD10 knockdown in endothelial cells, angiogenesis assays, gene/protein expression analysis, double knockdown epistasis (RAP1B + COMMD10)\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single KD approach with epistasis; no reconstitution or direct binding assay linking COMMD10 to Rap1 pathway components\",\n      \"pmids\": [\"40496352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COMMD10 is required for neural plate and neural crest development during embryogenesis; Commd10-deficient mouse embryos arrest by E8.5 with markedly reduced expression of neural crest transcription factors (including Sox10) and neurogenesis-related cytokines/growth factors, alongside upregulation of tissue remodeling and regression genes.\",\n      \"method\": \"Commd10 knockout mice (Vav1-cre–mediated functional KO in homozygotes), embryo phenotyping, transcriptome analysis\",\n      \"journal\": \"Journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with embryonic lethality phenotype and transcriptome characterization; mechanistic pathway placement is descriptive/transcriptomic rather than biochemical\",\n      \"pmids\": [\"36976102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COMMD10 promotes DNA damage repair and maintains genomic stability in gastric cancer cells. Knockdown of COMMD10 impairs DNA damage repair, intensifies DNA damage, and activates the ATM-p53 signaling pathway both in vitro and in xenograft tumors; restoration of COMMD10 suppresses DNA damage and ATM-p53 activation.\",\n      \"method\": \"COMMD10 knockdown and restoration in GC cell lines, in vivo xenograft tumor experiments, western blot, immunofluorescence for DNA damage markers, ATM-p53 pathway activation assays\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD/rescue approach with pathway activation assay; no direct biochemical mechanism linking COMMD10 to DNA repair machinery\",\n      \"pmids\": [\"38871970\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COMMD10 is a multifunctional regulator that (1) suppresses NF-κB signaling by binding p65 and reducing its nuclear translocation (and is itself degraded by FMNL2-mediated ubiquitination), (2) controls Cu/Fe homeostasis and HIF1α stability to modulate ferroptosis and radiosensitivity, (3) promotes phagolysosomal maturation and lysosomal biogenesis (via TFEB) in macrophages for bacterial clearance, (4) restrains inflammasome (caspase-1/11) activation in Ly6Chi monocytes, (5) supports tissue-resident macrophage survival, (6) positively regulates ENaC trafficking and current in epithelial cells by antagonizing Nedd4-2, (7) is essential for embryonic neural crest development, and (8) maintains genomic stability by supporting DNA damage repair through the ATM-p53 pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COMMD10 is a member of the COMMD/CCC complex that acts as a regulator of protein trafficking, metal homeostasis, and inflammatory signaling across epithelial and myeloid cell types [#2, #5]. It functions as a negative regulator of NF-\\u03baB signaling by binding the p65 subunit and reducing its nuclear translocation; this activity is itself controlled by FMNL2, which physically interacts with COMMD10 and targets it for ubiquitin-mediated proteasomal degradation [#1]. COMMD10 promotes the ubiquitin-dependent proteasomal degradation of HIF1\\u03b1 and constrains copper accumulation, and loss of this activity (for example following ionizing radiation) stabilizes HIF1\\u03b1 and drives transcription of ceruloplasmin and SLC7A11 to suppress ferroptosis [#0]. In macrophages, COMMD10 supports TFEB-driven lysosomal biogenesis and phagolysosomal maturation required for bacterial clearance, sustains tissue-resident macrophage survival, and restrains canonical and non-canonical inflammasome (caspase-1/11) activation in Ly6Chi monocytes [#2, #3, #4]. In epithelial cells COMMD10 binds the epithelial Na+ channel (ENaC) and positively regulates its current by antagonizing Nedd4-2 while also influencing endocytic trafficking [#5]. COMMD10 is essential for neural plate and neural crest development, with knockout embryos arresting by E8.5 and showing loss of neural crest transcription factors including Sox10 [#7].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established COMMD10 as a node controlling its own stability and NF-\\u03baB output, answering how an upstream factor (FMNL2) tunes inflammatory and metastatic signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pull-down, in vitro ubiquitination, and dual-luciferase reporter assays in colorectal cancer cells\",\n      \"pmids\": [\"28817833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain/residues mediating COMMD10\\u2013p65 binding not mapped\", \"Whether FMNL2 is the ubiquitin ligase or a recruiter not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a cell-type-specific role for COMMD10 as a brake on inflammasome activation, distinguishing its function in Ly6Chi monocytes from tissue-resident macrophages.\",\n      \"evidence\": \"Myeloid-specific conditional knockout with LPS and DSS colitis models and caspase-1/11 activation assays\",\n      \"pmids\": [\"30487795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which COMMD10 suppresses caspase activation unknown\", \"Direct inflammasome component interactions not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed COMMD10 physically interacts with ENaC and positively regulates channel current, linking it to Nedd4-2 antagonism and endocytic trafficking.\",\n      \"evidence\": \"Co-IP, stable shRNA knockdown in Fischer rat thyroid epithelia, electrophysiology, and transferrin trafficking assays\",\n      \"pmids\": [\"29997525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only partial functional rescue\", \"Mechanistic basis of Nedd4-2 antagonism not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed COMMD10 in phagolysosomal maturation via TFEB-driven lysosomal biogenesis and the CCC complex during bacterial infection.\",\n      \"evidence\": \"COMMD10-deficient macrophages/Kupffer cells, in vivo S. aureus infection, and TFEB activity assays\",\n      \"pmids\": [\"30959277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from COMMD10 to TFEB activation not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated COMMD10 is required for homeostatic survival of tissue-resident macrophages and shapes monocyte fate during liver injury.\",\n      \"evidence\": \"Conditional knockout mice, acetaminophen liver injury, inflammasome and type I IFN assays, fate-mapping\",\n      \"pmids\": [\"34788631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of survival dependence not biochemically defined\", \"Causal ordering between inflammasome derepression and fate skewing unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified COMMD10 as a regulator of HIF1\\u03b1 stability and copper homeostasis that controls ferroptosis and radiosensitivity in hepatocellular carcinoma.\",\n      \"evidence\": \"Western blot, qPCR, clonogenic radiation assays, lentivirus mouse models, and lipid peroxidation/Fe2+/Cu assays\",\n      \"pmids\": [\"35101526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution or mutagenesis of the COMMD10\\u2013HIF1\\u03b1 interaction\", \"Ubiquitin ligase involved not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established an essential developmental requirement for COMMD10 in neural plate and neural crest formation.\",\n      \"evidence\": \"Commd10 knockout mice with embryo phenotyping and transcriptome analysis\",\n      \"pmids\": [\"36976102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic placement is transcriptomic/descriptive rather than biochemical\", \"Specific COMMD10 targets driving neural crest gene loss unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked COMMD10 to maintenance of genomic stability through suppression of ATM-p53 signaling and support of DNA damage repair.\",\n      \"evidence\": \"Knockdown/restoration in gastric cancer cells, xenografts, and DNA damage marker/ATM-p53 assays\",\n      \"pmids\": [\"38871970\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical link to DNA repair machinery\", \"Single lab, KD/rescue only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated COMMD10 as a restraint on endothelial angiogenesis and osteogenic crosstalk via the Rap1 pathway.\",\n      \"evidence\": \"Endothelial knockdown, angiogenesis assays, and RAP1B/COMMD10 double-knockdown epistasis\",\n      \"pmids\": [\"40496352\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding assay linking COMMD10 to Rap1 components\", \"Single KD approach without reconstitution\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COMMD10's diverse roles (NF-\\u03baB, HIF1\\u03b1/copper, lysosomal/TFEB, ENaC trafficking, development, DNA repair) converge on a unifying biochemical activity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of COMMD10\", \"Whether all functions depend on the CCC complex unknown\", \"Direct enzymatic or adaptor activity not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"complexes\": [\"CCC (COMMD/CCDC22/CCDC93) complex\"],\n    \"partners\": [\"FMNL2\", \"RELA\", \"HIF1A\", \"ENaC\", \"NEDD4L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}