{"gene":"COMMD3","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2019,"finding":"The COMMD3/8 complex acts as a specificity adaptor that selectively recruits GRK6 to activated chemoattractant receptors (e.g., CXCR4), promoting GRK6-mediated receptor phosphorylation and β-arrestin-mediated signaling; COMMD8 stability depends on COMMD3, and deficiency of either COMMD3 or COMMD8 impairs B cell migration and humoral immune responses.","method":"Co-immunoprecipitation, genetic knockdown/knockout, in vivo B cell migration and humoral response assays, receptor phosphorylation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex composition, genetic loss-of-function with defined cellular phenotypes, receptor phosphorylation assay, and in vivo validation; multiple orthogonal methods in one study","pmids":["31088898"],"is_preprint":false},{"year":2023,"finding":"Celastrol covalently binds to and dissociates the COMMD3/8 complex, thereby inhibiting B cell migration and reducing antibody responses; mice expressing a celastrol-resistant mutant of COMMD3/8 were protected from celastrol's immunosuppressive effects, confirming that the COMMD3/8 complex is the direct molecular target of celastrol.","method":"Covalent binding assay, mutagenesis (celastrol-resistant mutant knock-in mice), B cell migration assays, in vivo arthritis model","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — covalent binding biochemistry, mutagenesis-based rescue in vivo, and multiple orthogonal functional assays across multiple models","pmids":["37000855"],"is_preprint":false},{"year":2013,"finding":"COMMD3 interacts with and downregulates the epithelial sodium channel (ENaC) by decreasing ENaC cell surface expression, reducing amiloride-sensitive current in mammalian epithelial cells; this effect is independent of COMMD1.","method":"Co-immunoprecipitation, electrophysiology (amiloride-sensitive current), surface biotinylation, COMMD1 knockdown","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, electrophysiology, and surface expression assay in a single lab; multiple methods but not independently replicated","pmids":["23637203"],"is_preprint":false},{"year":2022,"finding":"In megakaryocytes, COMMD3 is part of the CCC (COMMD/CCDC22/CCDC93) complex; COMMD3/CCC deficiency reduces α-granule numbers and overall levels of α-granule proteins, and P-selectin traffics through the cell surface in a COMMD3-dependent manner, with COMMD3 depletion causing lysosomal degradation of P-selectin and PF4.","method":"Co-immunoprecipitation, shRNA knockdown, flow cytometry, immunofluorescence, transmission electron microscopy of α-granules","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex, KD with defined organelle phenotype and cargo trafficking outcomes, multiple orthogonal methods in single lab","pmids":["34905616"],"is_preprint":false},{"year":2019,"finding":"COMMD3 protein is recruited to the promoter of the C-MYC gene (by ChIP analysis), and COMMD3 regulates C-MYC transcription and its downstream pathway in prostate cancer cells; a COMMD3:BMI1 fusion protein also regulates C-MYC transcription.","method":"ChIP assay, siRNA knockdown, gene expression analysis, xenograft mouse model","journal":"Molecular cancer therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and KD from a single lab with a single method per claim; no independent replication","pmids":["31467179"],"is_preprint":false},{"year":2023,"finding":"COMMD3 physically interacts with HER2 as a component of the Retriever-associated COMMD/CCDC22/CCDC93 (CCC) complex, directing HER2 to a slow recycling endosomal pathway and attenuating HER2 downstream tumor-promoting signaling in ovarian carcinoma cells.","method":"Genome-wide CRISPR/Cas9 screen, Co-immunoprecipitation, transcriptome analysis, in vivo orthotopic mouse model","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing COMMD3-HER2 interaction, functional KO with defined trafficking and signaling phenotype, in vivo validation; single lab","pmids":["36445330"],"is_preprint":false},{"year":2025,"finding":"COMMD3 has a Commander complex-independent function in endosomal recycling: its N-terminal domain (NTD) directly binds and stabilizes ARF1 (ADP-ribosylation factor 1), a small GTPase; mutations disrupting the COMMD3-NTD–ARF1 interaction diminish ARF1 expression and impair recycling of a subset of cargo proteins that are otherwise unaffected by loss of other Commander subunits.","method":"Unbiased genetic screens, comparative targeted mutagenesis, binding assays (COMMD3 NTD–ARF1 interaction), cargo recycling assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic screen plus mutagenesis defining domain requirement, direct binding assay, multiple orthogonal methods in single study; peer-reviewed publication","pmids":["40838988"],"is_preprint":false},{"year":2025,"finding":"COMMD3 has a Commander complex-independent function in endosomal recycling mediated by its N-terminal domain binding ARF1 (preprint version of the eLife finding above).","method":"Unbiased genetic screens, comparative targeted mutagenesis, binding assays, cargo recycling assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — same study as peer-reviewed eLife paper; included as preprint; confidence not independently elevated beyond the published version","pmids":["39763841"],"is_preprint":true},{"year":2023,"finding":"COMMD3 loss in breast cancer cells promotes invasive spheroid growth, and RNA sequencing revealed that COMMD3 regulates copper signaling via regulation of the Na+/K+-ATPase subunit ATP1B1; treatment of COMMD3-depleted cells with the copper chelator tetrathiomolybdate reduced invasive growth via apoptosis induction.","method":"shRNA knockdown, 3D on-top cellular assay, RNA sequencing, copper chelation rescue experiment, syngeneic mouse model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with defined phenotype, transcriptomics, and pharmacological rescue in a single lab; multiple methods","pmids":["37072858"],"is_preprint":false},{"year":2025,"finding":"COMMD3 regulates intracellular copper levels via the ATOX1-ATP7A-LOX copper-metabolism pathway in multiple myeloma cells; ATOX1 inhibition abolished COMMD3's pro-proliferative and pro-migratory effects, placing COMMD3 upstream of ATOX1 in this axis.","method":"Lentiviral overexpression/knockdown, RNA sequencing, intracellular copper measurement, ATOX1 inhibition rescue, xenograft NSG mouse model","journal":"Biomedicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis inferred from inhibitor rescue in single lab; copper measurement and in vivo validation present but no direct biochemical interaction shown between COMMD3 and ATOX1","pmids":["40002764"],"is_preprint":false},{"year":2026,"finding":"COMMD3 regulates melanogenesis through two mechanisms: (1) it controls intracellular copper levels (acting as a copper transporter), thereby modulating tyrosinase activity—COMMD3 deficiency causes intracellular copper accumulation that lowers tyrosinase activity; (2) it suppresses clusterin (CLU) expression, which otherwise reduces PAX3 nuclear translocation, thus COMMD3 promotes melanin synthesis via the CLU-PAX3 axis.","method":"Gene knockdown in B16F10 cells, RNA sequencing, intracellular copper measurement, copper chelation rescue (ammonium tetrathiomolybdate), UVB-induced pigmentation mouse model","journal":"Journal of dermatological science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with transcriptomics and pharmacological rescue; pathway placement based on indirect evidence without direct biochemical interaction between COMMD3 and copper transporters or CLU","pmids":["42150995"],"is_preprint":false},{"year":1992,"finding":"The BUP (now COMMD3) locus was identified as an unknown gene upstream of bmi-1 in the mouse proviral insertion locus; cDNA sequencing revealed at least 7 exons encoding a 195-amino-acid polypeptide with no homology to known proteins or conserved motifs at the time.","method":"cDNA cloning, genomic sequencing, computer sequence analysis","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 4 / Weak — sequence characterization only; no functional or mechanistic experiment performed on the protein","pmids":["1287475"],"is_preprint":false}],"current_model":"COMMD3 is a multifunctional adaptor protein that operates both as part of the COMMD3/8 heterocomplex—where it recruits GRK6 specifically to activated chemoattractant receptors to drive β-arrestin signaling and lymphocyte chemotaxis—and as a subunit of the broader Commander/CCC endosomal recycling complex, where its N-terminal domain independently binds and stabilizes the small GTPase ARF1 to recycle a subset of membrane cargo proteins (including HER2) through the slow endosomal recycling pathway; additionally, COMMD3 modulates intracellular copper homeostasis to influence tyrosinase activity and downstream copper-dependent enzymes, and reduces epithelial sodium channel (ENaC) surface expression to regulate sodium transport."},"narrative":{"mechanistic_narrative":"COMMD3 is a multifunctional adaptor protein that operates in receptor signaling and endosomal membrane trafficking [PMID:31088898, PMID:40838988]. As an obligate partner in the COMMD3/8 heterocomplex, it functions as a specificity adaptor that selectively recruits GRK6 to activated chemoattractant receptors such as CXCR4, driving receptor phosphorylation and β-arrestin-mediated signaling required for B cell migration and humoral immune responses; COMMD8 stability is itself dependent on COMMD3 [PMID:31088898]. This complex is the direct covalent target of celastrol, whose immunosuppressive action depends on dissociating COMMD3/8 [PMID:37000855]. COMMD3 is also a subunit of the broader COMMD/CCDC22/CCDC93 (CCC) complex that directs membrane cargo through endosomal recycling pathways, controlling trafficking of cargo including HER2 into a slow recycling route and of P-selectin away from lysosomal degradation in megakaryocyte α-granule biogenesis [PMID:34905616, PMID:36445330]. Beyond the Commander complex, the COMMD3 N-terminal domain independently binds and stabilizes the small GTPase ARF1 to recycle a distinct subset of cargo proteins unaffected by loss of other Commander subunits [PMID:40838988]. COMMD3 additionally modulates membrane protein abundance more broadly, downregulating epithelial sodium channel (ENaC) surface expression independently of COMMD1 [PMID:23637203]. A recurrent theme across cancer models links COMMD3 to intracellular copper homeostasis and copper-dependent enzyme activity [PMID:37072858, PMID:42150995].","teleology":[{"year":1992,"claim":"Before any function was known, the gene now called COMMD3 had to be cloned and placed in the genome; this established its existence as a distinct locus encoding a novel protein.","evidence":"cDNA cloning and genomic sequencing of the BUP locus upstream of bmi-1 in mouse","pmids":["1287475"],"confidence":"Low","gaps":["No functional or mechanistic role assigned","No conserved motifs or homology identifiable at the time","Protein product uncharacterized"]},{"year":2013,"claim":"The first mechanistic role addressed whether COMMD3 regulates membrane transporter surface levels, showing it can downregulate ENaC independently of COMMD1.","evidence":"Co-IP, surface biotinylation, and amiloride-sensitive current electrophysiology with COMMD1 knockdown in epithelial cells","pmids":["23637203"],"confidence":"Medium","gaps":["Mechanism of ENaC surface reduction not resolved","Not independently replicated","Relationship to later-defined CCC/recycling role unaddressed"]},{"year":2019,"claim":"A defining function emerged with the discovery that COMMD3/8 acts as a specificity adaptor recruiting GRK6 to chemoattractant receptors, establishing a direct role in GPCR signaling and lymphocyte chemotaxis.","evidence":"Reciprocal Co-IP, genetic knockout, receptor phosphorylation assays, and in vivo B cell migration and humoral response assays","pmids":["31088898"],"confidence":"High","gaps":["Structural basis of GRK6 selectivity not defined","Range of receptors served by COMMD3/8 not fully mapped","Connection to broader Commander/CCC role unclear"]},{"year":2019,"claim":"A separate line tested whether COMMD3 acts in transcriptional control of oncogenes, reporting recruitment to the C-MYC promoter in prostate cancer cells.","evidence":"ChIP, siRNA knockdown, expression analysis, and xenograft model","pmids":["31467179"],"confidence":"Low","gaps":["Single method per claim with no independent replication","Direct vs indirect promoter occupancy not distinguished","Hard to reconcile with cytoplasmic/endosomal roles"]},{"year":2022,"claim":"COMMD3 was placed within the CCC complex in megakaryocytes, linking it to cargo trafficking and organelle biogenesis by showing it protects P-selectin and PF4 from lysosomal degradation during α-granule formation.","evidence":"Co-IP, shRNA knockdown, flow cytometry, immunofluorescence, and TEM of α-granules","pmids":["34905616"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Direct cargo-binding mechanism not established","Scope of affected cargoes beyond P-selectin/PF4 unclear"]},{"year":2023,"claim":"The Commander/CCC trafficking role was extended to cancer-relevant cargo, identifying COMMD3 as directing HER2 into a slow recycling pathway to attenuate tumor-promoting signaling.","evidence":"Genome-wide CRISPR screen, Co-IP, transcriptome analysis, and orthotopic mouse model in ovarian carcinoma","pmids":["36445330"],"confidence":"Medium","gaps":["Direct vs complex-mediated HER2 binding not separated","Single lab","Generality of slow-recycling routing across cargoes unknown"]},{"year":2023,"claim":"The pharmacology of COMMD3/8 was defined by showing celastrol covalently binds and dissociates the complex, with a resistant mutant conferring protection in vivo, confirming COMMD3/8 as celastrol's direct target.","evidence":"Covalent binding biochemistry, celastrol-resistant knock-in mice, B cell migration assays, and in vivo arthritis model","pmids":["37000855"],"confidence":"High","gaps":["Precise covalent residue/site not detailed here","Downstream signaling consequences beyond migration not fully mapped"]},{"year":2023,"claim":"A copper-homeostasis link was proposed, with COMMD3 loss promoting invasive breast cancer growth via regulation of the Na+/K+-ATPase subunit ATP1B1 and copper signaling.","evidence":"shRNA knockdown, 3D assay, RNA-seq, copper chelation rescue, and syngeneic mouse model","pmids":["37072858"],"confidence":"Medium","gaps":["No direct biochemical interaction with copper machinery shown","Single lab","Causal chain from ATP1B1 to copper to invasion inferred"]},{"year":2025,"claim":"A Commander complex-independent activity was defined: the COMMD3 N-terminal domain directly binds and stabilizes ARF1 to recycle a subset of cargo not served by other Commander subunits, distinguishing two separable trafficking functions.","evidence":"Unbiased genetic screens, comparative targeted mutagenesis, direct binding assays, and cargo recycling assays","pmids":["40838988","39763841"],"confidence":"High","gaps":["Identity of the ARF1-dependent cargo subset not fully enumerated","Structural detail of the NTD–ARF1 interface limited","How the two COMMD3 trafficking modes are coordinated unknown"]},{"year":2025,"claim":"The copper axis was extended to multiple myeloma, placing COMMD3 upstream of ATOX1 in an ATOX1-ATP7A-LOX copper-metabolism pathway.","evidence":"Lentiviral over/knockdown, RNA-seq, intracellular copper measurement, ATOX1 inhibition rescue, and xenograft model","pmids":["40002764"],"confidence":"Low","gaps":["Epistasis inferred from inhibitor rescue without direct COMMD3–ATOX1 interaction","Single lab","Mechanism of copper level control unresolved"]},{"year":2026,"claim":"A pigmentation role was reported, with COMMD3 controlling intracellular copper to modulate tyrosinase activity and acting via a CLU-PAX3 axis to promote melanogenesis.","evidence":"Knockdown in B16F10 cells, RNA-seq, copper measurement, chelation rescue, and UVB pigmentation mouse model","pmids":["42150995"],"confidence":"Low","gaps":["Pathway placement based on indirect evidence","No direct biochemical interaction with copper transporters or CLU shown","Single lab"]},{"year":null,"claim":"How COMMD3's distinct activities—GRK6/β-arrestin adaptation, CCC-dependent and ARF1-dependent recycling, and copper homeostasis—are mechanistically integrated within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model unifying COMMD3 domains across functions","Whether copper regulation is direct or a downstream trafficking consequence is unknown","Cross-talk between Commander-dependent and -independent recycling not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,5,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":["COMMD3/8 complex","Commander/CCC (COMMD/CCDC22/CCDC93) complex"],"partners":["COMMD8","GRK6","ARF1","HER2","ENAC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBI1","full_name":"COMM domain-containing protein 3","aliases":["Protein Bup","Protein PIL"],"length_aa":195,"mass_kda":22.2,"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). Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits (PubMed:23637203)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UBI1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COMMD3","classification":"Not Classified","n_dependent_lines":114,"n_total_lines":1208,"dependency_fraction":0.09437086092715231},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COMMD3","total_profiled":1310},"omim":[{"mim_id":"616700","title":"COMM DOMAIN-CONTAINING PROTEIN 3; COMMD3","url":"https://www.omim.org/entry/616700"},{"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":"606892","title":"SYNTAXIN 12; STX12","url":"https://www.omim.org/entry/606892"}],"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/COMMD3"},"hgnc":{"alias_symbol":["BUP"],"prev_symbol":["C10orf8"]},"alphafold":{"accession":"Q9UBI1","domains":[{"cath_id":"-","chopping":"6-118","consensus_level":"high","plddt":91.1569,"start":6,"end":118},{"cath_id":"-","chopping":"122-174","consensus_level":"medium","plddt":78.5072,"start":122,"end":174}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBI1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBI1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBI1-F1-predicted_aligned_error_v6.png","plddt_mean":87.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COMMD3","jax_strain_url":"https://www.jax.org/strain/search?query=COMMD3"},"sequence":{"accession":"Q9UBI1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBI1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBI1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBI1"}},"corpus_meta":[{"pmid":"37000855","id":"PMC_37000855","title":"Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex.","date":"2023","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37000855","citation_count":44,"is_preprint":false},{"pmid":"31088898","id":"PMC_31088898","title":"The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31088898","citation_count":36,"is_preprint":false},{"pmid":"10542323","id":"PMC_10542323","title":"cDNA cloning, genomic structure and chromosomal localization of the human BUP-1 gene encoding beta-ureidopropionase.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10542323","citation_count":31,"is_preprint":false},{"pmid":"23637203","id":"PMC_23637203","title":"Functional interaction of COMMD3 and COMMD9 with the epithelial sodium channel.","date":"2013","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23637203","citation_count":27,"is_preprint":false},{"pmid":"34905616","id":"PMC_34905616","title":"Syntaxin 12 and COMMD3 are new factors that function with VPS33B in the biogenesis of platelet α-granules.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34905616","citation_count":21,"is_preprint":false},{"pmid":"7572774","id":"PMC_7572774","title":"Delayed cutaneous hypersensitivity reactions in Qigong (chun do sun bup) trainees by multitest cell mediated immunity.","date":"1995","source":"The American journal of Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7572774","citation_count":21,"is_preprint":false},{"pmid":"31467179","id":"PMC_31467179","title":"COMMD3:BMI1 Fusion and COMMD3 Protein Regulate C-MYC Transcription: Novel Therapeutic Target for Metastatic Prostate Cancer.","date":"2019","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31467179","citation_count":20,"is_preprint":false},{"pmid":"37072858","id":"PMC_37072858","title":"COMMD3 loss drives invasive breast cancer growth by modulating copper homeostasis.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37072858","citation_count":15,"is_preprint":false},{"pmid":"36092163","id":"PMC_36092163","title":"COMMD3 Expression Affects Angiogenesis through the HIF1α/VEGF/NF-κB Signaling Pathway in Hepatocellular Carcinoma In Vitro and In Vivo.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36092163","citation_count":12,"is_preprint":false},{"pmid":"1287475","id":"PMC_1287475","title":"Nucleotide sequence of bup, an upstream gene in the bmi-1 proviral insertion locus.","date":"1992","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/1287475","citation_count":7,"is_preprint":false},{"pmid":"40002764","id":"PMC_40002764","title":"COMMD3 Regulates Copper Metabolism via the ATOX1-ATP7A-LOX Axis to Promote Multiple Myeloma Progression.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40002764","citation_count":6,"is_preprint":false},{"pmid":"36445330","id":"PMC_36445330","title":"COMMD3-Mediated Endosomal Trafficking of HER2 Inhibits the Progression of Ovarian Carcinoma.","date":"2023","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/36445330","citation_count":5,"is_preprint":false},{"pmid":"40838988","id":"PMC_40838988","title":"A Commander-independent function of COMMD3 in endosomal trafficking.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/40838988","citation_count":0,"is_preprint":false},{"pmid":"39763841","id":"PMC_39763841","title":"A Commander-independent function of COMMD3 in endosomal trafficking.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39763841","citation_count":0,"is_preprint":false},{"pmid":"42150995","id":"PMC_42150995","title":"COMMD3 mediates melanin synthesis through both clusterin-PAX3 axis and copper-dependent tyrosinase activity in skin pigmentation.","date":"2026","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/42150995","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.26.25340877","title":"HIV pre-exposure prophylaxis among people initiating buprenorphine for opioid use disorder: a retrospective cohort study","date":"2025-11-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.25340877","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.06.25337456","title":"Total-body [11C]carfentanil PET: liver-brain axis in methadone vs. buprenorphine treatment.","date":"2025-10-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.06.25337456","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10987,"output_tokens":3027,"usd":0.039183,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10517,"output_tokens":3794,"usd":0.073718,"stage2_stop_reason":"end_turn"},"total_usd":0.112901,"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\": 2019,\n      \"finding\": \"The COMMD3/8 complex acts as a specificity adaptor that selectively recruits GRK6 to activated chemoattractant receptors (e.g., CXCR4), promoting GRK6-mediated receptor phosphorylation and β-arrestin-mediated signaling; COMMD8 stability depends on COMMD3, and deficiency of either COMMD3 or COMMD8 impairs B cell migration and humoral immune responses.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockdown/knockout, in vivo B cell migration and humoral response assays, receptor phosphorylation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex composition, genetic loss-of-function with defined cellular phenotypes, receptor phosphorylation assay, and in vivo validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"31088898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celastrol covalently binds to and dissociates the COMMD3/8 complex, thereby inhibiting B cell migration and reducing antibody responses; mice expressing a celastrol-resistant mutant of COMMD3/8 were protected from celastrol's immunosuppressive effects, confirming that the COMMD3/8 complex is the direct molecular target of celastrol.\",\n      \"method\": \"Covalent binding assay, mutagenesis (celastrol-resistant mutant knock-in mice), B cell migration assays, in vivo arthritis model\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — covalent binding biochemistry, mutagenesis-based rescue in vivo, and multiple orthogonal functional assays across multiple models\",\n      \"pmids\": [\"37000855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COMMD3 interacts with and downregulates the epithelial sodium channel (ENaC) by decreasing ENaC cell surface expression, reducing amiloride-sensitive current in mammalian epithelial cells; this effect is independent of COMMD1.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology (amiloride-sensitive current), surface biotinylation, COMMD1 knockdown\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, electrophysiology, and surface expression assay in a single lab; multiple methods but not independently replicated\",\n      \"pmids\": [\"23637203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In megakaryocytes, COMMD3 is part of the CCC (COMMD/CCDC22/CCDC93) complex; COMMD3/CCC deficiency reduces α-granule numbers and overall levels of α-granule proteins, and P-selectin traffics through the cell surface in a COMMD3-dependent manner, with COMMD3 depletion causing lysosomal degradation of P-selectin and PF4.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, flow cytometry, immunofluorescence, transmission electron microscopy of α-granules\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex, KD with defined organelle phenotype and cargo trafficking outcomes, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"34905616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"COMMD3 protein is recruited to the promoter of the C-MYC gene (by ChIP analysis), and COMMD3 regulates C-MYC transcription and its downstream pathway in prostate cancer cells; a COMMD3:BMI1 fusion protein also regulates C-MYC transcription.\",\n      \"method\": \"ChIP assay, siRNA knockdown, gene expression analysis, xenograft mouse model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and KD from a single lab with a single method per claim; no independent replication\",\n      \"pmids\": [\"31467179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COMMD3 physically interacts with HER2 as a component of the Retriever-associated COMMD/CCDC22/CCDC93 (CCC) complex, directing HER2 to a slow recycling endosomal pathway and attenuating HER2 downstream tumor-promoting signaling in ovarian carcinoma cells.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, Co-immunoprecipitation, transcriptome analysis, in vivo orthotopic mouse model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing COMMD3-HER2 interaction, functional KO with defined trafficking and signaling phenotype, in vivo validation; single lab\",\n      \"pmids\": [\"36445330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COMMD3 has a Commander complex-independent function in endosomal recycling: its N-terminal domain (NTD) directly binds and stabilizes ARF1 (ADP-ribosylation factor 1), a small GTPase; mutations disrupting the COMMD3-NTD–ARF1 interaction diminish ARF1 expression and impair recycling of a subset of cargo proteins that are otherwise unaffected by loss of other Commander subunits.\",\n      \"method\": \"Unbiased genetic screens, comparative targeted mutagenesis, binding assays (COMMD3 NTD–ARF1 interaction), cargo recycling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic screen plus mutagenesis defining domain requirement, direct binding assay, multiple orthogonal methods in single study; peer-reviewed publication\",\n      \"pmids\": [\"40838988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COMMD3 has a Commander complex-independent function in endosomal recycling mediated by its N-terminal domain binding ARF1 (preprint version of the eLife finding above).\",\n      \"method\": \"Unbiased genetic screens, comparative targeted mutagenesis, binding assays, cargo recycling assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — same study as peer-reviewed eLife paper; included as preprint; confidence not independently elevated beyond the published version\",\n      \"pmids\": [\"39763841\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COMMD3 loss in breast cancer cells promotes invasive spheroid growth, and RNA sequencing revealed that COMMD3 regulates copper signaling via regulation of the Na+/K+-ATPase subunit ATP1B1; treatment of COMMD3-depleted cells with the copper chelator tetrathiomolybdate reduced invasive growth via apoptosis induction.\",\n      \"method\": \"shRNA knockdown, 3D on-top cellular assay, RNA sequencing, copper chelation rescue experiment, syngeneic mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with defined phenotype, transcriptomics, and pharmacological rescue in a single lab; multiple methods\",\n      \"pmids\": [\"37072858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COMMD3 regulates intracellular copper levels via the ATOX1-ATP7A-LOX copper-metabolism pathway in multiple myeloma cells; ATOX1 inhibition abolished COMMD3's pro-proliferative and pro-migratory effects, placing COMMD3 upstream of ATOX1 in this axis.\",\n      \"method\": \"Lentiviral overexpression/knockdown, RNA sequencing, intracellular copper measurement, ATOX1 inhibition rescue, xenograft NSG mouse model\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis inferred from inhibitor rescue in single lab; copper measurement and in vivo validation present but no direct biochemical interaction shown between COMMD3 and ATOX1\",\n      \"pmids\": [\"40002764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"COMMD3 regulates melanogenesis through two mechanisms: (1) it controls intracellular copper levels (acting as a copper transporter), thereby modulating tyrosinase activity—COMMD3 deficiency causes intracellular copper accumulation that lowers tyrosinase activity; (2) it suppresses clusterin (CLU) expression, which otherwise reduces PAX3 nuclear translocation, thus COMMD3 promotes melanin synthesis via the CLU-PAX3 axis.\",\n      \"method\": \"Gene knockdown in B16F10 cells, RNA sequencing, intracellular copper measurement, copper chelation rescue (ammonium tetrathiomolybdate), UVB-induced pigmentation mouse model\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with transcriptomics and pharmacological rescue; pathway placement based on indirect evidence without direct biochemical interaction between COMMD3 and copper transporters or CLU\",\n      \"pmids\": [\"42150995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The BUP (now COMMD3) locus was identified as an unknown gene upstream of bmi-1 in the mouse proviral insertion locus; cDNA sequencing revealed at least 7 exons encoding a 195-amino-acid polypeptide with no homology to known proteins or conserved motifs at the time.\",\n      \"method\": \"cDNA cloning, genomic sequencing, computer sequence analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — sequence characterization only; no functional or mechanistic experiment performed on the protein\",\n      \"pmids\": [\"1287475\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COMMD3 is a multifunctional adaptor protein that operates both as part of the COMMD3/8 heterocomplex—where it recruits GRK6 specifically to activated chemoattractant receptors to drive β-arrestin signaling and lymphocyte chemotaxis—and as a subunit of the broader Commander/CCC endosomal recycling complex, where its N-terminal domain independently binds and stabilizes the small GTPase ARF1 to recycle a subset of membrane cargo proteins (including HER2) through the slow endosomal recycling pathway; additionally, COMMD3 modulates intracellular copper homeostasis to influence tyrosinase activity and downstream copper-dependent enzymes, and reduces epithelial sodium channel (ENaC) surface expression to regulate sodium transport.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COMMD3 is a multifunctional adaptor protein that operates in receptor signaling and endosomal membrane trafficking [#0, #6]. As an obligate partner in the COMMD3/8 heterocomplex, it functions as a specificity adaptor that selectively recruits GRK6 to activated chemoattractant receptors such as CXCR4, driving receptor phosphorylation and β-arrestin-mediated signaling required for B cell migration and humoral immune responses; COMMD8 stability is itself dependent on COMMD3 [#0]. This complex is the direct covalent target of celastrol, whose immunosuppressive action depends on dissociating COMMD3/8 [#1]. COMMD3 is also a subunit of the broader COMMD/CCDC22/CCDC93 (CCC) complex that directs membrane cargo through endosomal recycling pathways, controlling trafficking of cargo including HER2 into a slow recycling route and of P-selectin away from lysosomal degradation in megakaryocyte α-granule biogenesis [#3, #5]. Beyond the Commander complex, the COMMD3 N-terminal domain independently binds and stabilizes the small GTPase ARF1 to recycle a distinct subset of cargo proteins unaffected by loss of other Commander subunits [#6]. COMMD3 additionally modulates membrane protein abundance more broadly, downregulating epithelial sodium channel (ENaC) surface expression independently of COMMD1 [#2]. A recurrent theme across cancer models links COMMD3 to intracellular copper homeostasis and copper-dependent enzyme activity [#8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Before any function was known, the gene now called COMMD3 had to be cloned and placed in the genome; this established its existence as a distinct locus encoding a novel protein.\",\n      \"evidence\": \"cDNA cloning and genomic sequencing of the BUP locus upstream of bmi-1 in mouse\",\n      \"pmids\": [\"1287475\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional or mechanistic role assigned\", \"No conserved motifs or homology identifiable at the time\", \"Protein product uncharacterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The first mechanistic role addressed whether COMMD3 regulates membrane transporter surface levels, showing it can downregulate ENaC independently of COMMD1.\",\n      \"evidence\": \"Co-IP, surface biotinylation, and amiloride-sensitive current electrophysiology with COMMD1 knockdown in epithelial cells\",\n      \"pmids\": [\"23637203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ENaC surface reduction not resolved\", \"Not independently replicated\", \"Relationship to later-defined CCC/recycling role unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A defining function emerged with the discovery that COMMD3/8 acts as a specificity adaptor recruiting GRK6 to chemoattractant receptors, establishing a direct role in GPCR signaling and lymphocyte chemotaxis.\",\n      \"evidence\": \"Reciprocal Co-IP, genetic knockout, receptor phosphorylation assays, and in vivo B cell migration and humoral response assays\",\n      \"pmids\": [\"31088898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GRK6 selectivity not defined\", \"Range of receptors served by COMMD3/8 not fully mapped\", \"Connection to broader Commander/CCC role unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A separate line tested whether COMMD3 acts in transcriptional control of oncogenes, reporting recruitment to the C-MYC promoter in prostate cancer cells.\",\n      \"evidence\": \"ChIP, siRNA knockdown, expression analysis, and xenograft model\",\n      \"pmids\": [\"31467179\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method per claim with no independent replication\", \"Direct vs indirect promoter occupancy not distinguished\", \"Hard to reconcile with cytoplasmic/endosomal roles\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"COMMD3 was placed within the CCC complex in megakaryocytes, linking it to cargo trafficking and organelle biogenesis by showing it protects P-selectin and PF4 from lysosomal degradation during α-granule formation.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, flow cytometry, immunofluorescence, and TEM of α-granules\",\n      \"pmids\": [\"34905616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Direct cargo-binding mechanism not established\", \"Scope of affected cargoes beyond P-selectin/PF4 unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The Commander/CCC trafficking role was extended to cancer-relevant cargo, identifying COMMD3 as directing HER2 into a slow recycling pathway to attenuate tumor-promoting signaling.\",\n      \"evidence\": \"Genome-wide CRISPR screen, Co-IP, transcriptome analysis, and orthotopic mouse model in ovarian carcinoma\",\n      \"pmids\": [\"36445330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs complex-mediated HER2 binding not separated\", \"Single lab\", \"Generality of slow-recycling routing across cargoes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The pharmacology of COMMD3/8 was defined by showing celastrol covalently binds and dissociates the complex, with a resistant mutant conferring protection in vivo, confirming COMMD3/8 as celastrol's direct target.\",\n      \"evidence\": \"Covalent binding biochemistry, celastrol-resistant knock-in mice, B cell migration assays, and in vivo arthritis model\",\n      \"pmids\": [\"37000855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise covalent residue/site not detailed here\", \"Downstream signaling consequences beyond migration not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A copper-homeostasis link was proposed, with COMMD3 loss promoting invasive breast cancer growth via regulation of the Na+/K+-ATPase subunit ATP1B1 and copper signaling.\",\n      \"evidence\": \"shRNA knockdown, 3D assay, RNA-seq, copper chelation rescue, and syngeneic mouse model\",\n      \"pmids\": [\"37072858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction with copper machinery shown\", \"Single lab\", \"Causal chain from ATP1B1 to copper to invasion inferred\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A Commander complex-independent activity was defined: the COMMD3 N-terminal domain directly binds and stabilizes ARF1 to recycle a subset of cargo not served by other Commander subunits, distinguishing two separable trafficking functions.\",\n      \"evidence\": \"Unbiased genetic screens, comparative targeted mutagenesis, direct binding assays, and cargo recycling assays\",\n      \"pmids\": [\"40838988\", \"39763841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ARF1-dependent cargo subset not fully enumerated\", \"Structural detail of the NTD–ARF1 interface limited\", \"How the two COMMD3 trafficking modes are coordinated unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The copper axis was extended to multiple myeloma, placing COMMD3 upstream of ATOX1 in an ATOX1-ATP7A-LOX copper-metabolism pathway.\",\n      \"evidence\": \"Lentiviral over/knockdown, RNA-seq, intracellular copper measurement, ATOX1 inhibition rescue, and xenograft model\",\n      \"pmids\": [\"40002764\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Epistasis inferred from inhibitor rescue without direct COMMD3–ATOX1 interaction\", \"Single lab\", \"Mechanism of copper level control unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A pigmentation role was reported, with COMMD3 controlling intracellular copper to modulate tyrosinase activity and acting via a CLU-PAX3 axis to promote melanogenesis.\",\n      \"evidence\": \"Knockdown in B16F10 cells, RNA-seq, copper measurement, chelation rescue, and UVB pigmentation mouse model\",\n      \"pmids\": [\"42150995\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement based on indirect evidence\", \"No direct biochemical interaction with copper transporters or CLU shown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COMMD3's distinct activities—GRK6/β-arrestin adaptation, CCC-dependent and ARF1-dependent recycling, and copper homeostasis—are mechanistically integrated within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model unifying COMMD3 domains across functions\", \"Whether copper regulation is direct or a downstream trafficking consequence is unknown\", \"Cross-talk between Commander-dependent and -independent recycling not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"COMMD3/8 complex\", \"Commander/CCC (COMMD/CCDC22/CCDC93) complex\"],\n    \"partners\": [\"COMMD8\", \"GRK6\", \"ARF1\", \"HER2\", \"ENaC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}