{"gene":"COMMD9","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2015,"finding":"COMMD9, together with its binding partner COMMD5, is specifically required within the CCC (COMMD-CCDC22-CCDC93) complex for endosomal recycling of Notch receptors to the cell surface; disruption of COMMD9 causes intracellular accumulation of Notch2 and reduced Notch signaling, while Commd9 deletion in mice causes embryonic lethality with cardiovascular defects bearing hallmarks of Notch deficiency.","method":"siRNA knockdown, co-immunoprecipitation, fluorescence microscopy of Notch2 trafficking, Commd9 conditional knockout mouse with phenotypic analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, live-cell trafficking imaging, and in vivo genetic model with specific phenotypic readout across multiple orthogonal methods in one study","pmids":["26553930"],"is_preprint":false},{"year":2016,"finding":"The CCC complex (containing COMMD9) and the WASH complex cooperate to mediate endosomal sorting of LDLR back to the cell surface; hepatic COMMD9 deficiency in mice leads to LDLR mislocalization, increased lysosomal degradation of LDLR, impaired LDL uptake, and elevated plasma LDL cholesterol levels.","method":"Liver-specific Commd9 knockout mice, plasma cholesterol measurements, LDLR localization by microscopy, LDL uptake assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo liver-specific KO with defined receptor trafficking and cholesterol phenotype, replicated across multiple COMMD family members and independent labs","pmids":["26965651"],"is_preprint":false},{"year":2016,"finding":"COMMD9 interacts with TFDP1 (DP1) through its COMM domain; the DNA-binding domain of TFDP1 is required for this interaction; COMMD9 promotes TFDP1/E2F1 transcriptional activity, and COMMD9 knockdown attenuates TFDP1/E2F1 activation and enhances p53 signaling in NSCLC cells, arresting the cell cycle at G1/S.","method":"Co-immunoprecipitation, domain-deletion mapping, siRNA knockdown with luciferase reporter assays, cell cycle analysis, and autophagy assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with domain mapping and functional reporter assays in a single lab, multiple orthogonal cellular readouts","pmids":["27871936"],"is_preprint":false},{"year":2018,"finding":"COMMD9 (like COMMD1 and COMMD6) is required for the stability of the entire COMMD protein family and the core CCC complex (CCDC22, CCDC93, C16orf62); hepatic Commd9 knockout causes massive reduction in all 10 COMMD protein levels, destabilization of the CCC core, reduced cell-surface levels of LDLR and LRP1, hypercholesterolemia, and accelerated atherosclerosis.","method":"Liver-specific Commd9 knockout mice, quantitative targeted proteomics, Western blotting, cell surface receptor quantification, plasma lipid measurements, atherosclerosis assessment in ApoE3*Leiden mice","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with quantitative proteomics and multiple orthogonal functional readouts, independently confirmed across three COMMD family members","pmids":["29545368"],"is_preprint":false},{"year":2013,"finding":"COMMD9 interacts with the epithelial sodium channel (ENaC) and reduces amiloride-sensitive current by decreasing ENaC cell surface expression; this effect is retained when COMMD1 is knocked down, indicating a COMMD1-independent mechanism.","method":"Co-immunoprecipitation, electrophysiological current measurement (Ussing chamber), cell surface biotinylation, COMMD1 siRNA knockdown, immunofluorescence colocalization in renal collecting duct cells","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, functional current assay, and surface expression assay in single lab with multiple orthogonal methods","pmids":["23637203"],"is_preprint":false},{"year":2021,"finding":"Hepatic Commd9 deficiency (like Commd1 and Commd6 deficiency) causes destabilization of the entire CCC complex and leads to hepatic copper accumulation under high-copper diets, consistent with impaired ATP7B endosomal recycling; by contrast, enterocyte-specific Commd9 deficiency does not significantly alter ATP7A regulation or intestinal copper absorption.","method":"Hepatocyte-specific and enterocyte-specific Commd9 knockout mice, tissue copper level measurements, Western blotting for CCC complex components, ATP7B localization","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tissue-specific KO with biochemical and metal-level readouts, single lab","pmids":["33262129"],"is_preprint":false},{"year":2025,"finding":"Pathogenic mutations in COMMD9 (identified in Ritscher-Schinzel syndrome patients) disrupt Commander complex assembly; interactome analysis showed reduced binding of mutant COMMD9 to Commander subunits, and cell surface proteomics showed tissue-specific reduction in presentation of integral membrane proteins containing ΦxNPxY/F or ΦxNxxY/F sorting motifs recognized by SNX17, establishing COMMD9 as essential for SNX17-dependent endosomal recycling of multiple cargo proteins critical for kidney, bone, and brain development.","method":"Patient genetic analysis, interactome/co-immunoprecipitation assays, cell surface proteomics, mouse models of RSS with proteinuria, skeletal malformation, and neurological phenotypes","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — interactome analysis combined with cell surface proteomics, patient mutations, and in vivo mouse models with multiple orthogonal readouts in one study","pmids":["40601774"],"is_preprint":false},{"year":2022,"finding":"Silencing of COMMD9 abrogates ETV6 repressive transcriptional activity in pre-B acute lymphoblastic leukemia cells, identifying COMMD9 as a modulator of ETV6 function.","method":"Genome-wide shRNA screen in pre-B ALL cells followed by validation of ETV6 target gene expression upon COMMD9 knockdown","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional screen readout with limited mechanistic follow-up; no biochemical binding or pathway placement beyond reporter gene expression","pmids":["35198911"],"is_preprint":false}],"current_model":"COMMD9 is an obligate subunit of the CCC (COMMD-CCDC22-CCDC93) Commander complex required for SNX17-dependent endosomal recycling of multiple cell-surface receptors including LDLR, LRP1, ATP7B, Notch2, and ENaC; it stabilizes the entire COMMD protein family and CCC core, and its loss causes receptor mislocalization, lysosomal degradation, hypercholesterolemia, copper accumulation, impaired Notch signaling, and—via patient mutations—Ritscher-Schinzel syndrome; additionally, COMMD9 promotes TFDP1/E2F1 transcriptional activity through a direct COMM-domain interaction with TFDP1."},"narrative":{"mechanistic_narrative":"COMMD9 is an obligate subunit of the CCC (COMMD-CCDC22-CCDC93) Commander complex that drives SNX17-dependent endosomal recycling of multiple cell-surface receptors, returning internalized cargo to the plasma membrane and preventing their lysosomal degradation [PMID:26965651, PMID:40601774]. It is structurally central to the system: hepatic loss of COMMD9 collapses the levels of the entire COMMD protein family and destabilizes the CCC core (CCDC22, CCDC93, C16orf62), establishing COMMD9 as a stability determinant for the whole assembly rather than a single-cargo adaptor [PMID:29545368]. Through this recycling function it controls the surface presentation of cargo bearing SNX17-recognized ΦxNPxY/F sorting motifs, including LDLR and LRP1, so that COMMD9 deficiency causes receptor mislocalization, impaired LDL uptake, hypercholesterolemia, and accelerated atherosclerosis [PMID:26965651, PMID:29545368, PMID:40601774]. The same machinery recycles ATP7B, and hepatic Commd9 loss produces copper accumulation under high-copper conditions [PMID:33262129], and recycles Notch2, whose intracellular accumulation upon COMMD9 disruption reduces Notch signaling and underlies embryonic cardiovascular defects [PMID:26553930]; COMMD9 also negatively regulates ENaC surface expression and amiloride-sensitive current through a COMMD1-independent mechanism [PMID:23637203]. Pathogenic COMMD9 mutations that impair Commander assembly cause Ritscher-Schinzel syndrome with kidney, bone, and brain involvement [PMID:40601774]. Beyond its endosomal role, COMMD9 interacts with TFDP1 via its COMM domain to promote TFDP1/E2F1 transcriptional activity, with its loss attenuating this output and enhancing p53 signaling to arrest the cell cycle at G1/S [PMID:27871936].","teleology":[{"year":2013,"claim":"Established a discrete cellular consequence of COMMD9 action on a membrane channel, showing it limits ENaC surface expression independently of COMMD1 and hinting at a broader role in receptor surface regulation.","evidence":"Co-IP, Ussing chamber current measurement, surface biotinylation, and COMMD1 knockdown in renal collecting duct cells","pmids":["23637203"],"confidence":"Medium","gaps":["Did not place COMMD9 within the CCC complex or define the recycling step affecting ENaC","Mechanism of COMMD1-independent action not resolved"]},{"year":2015,"claim":"Defined COMMD9 as a CCC-complex factor required for recycling Notch receptors to the surface, linking its molecular trafficking role to an essential developmental signaling pathway in vivo.","evidence":"siRNA knockdown, co-IP, Notch2 trafficking microscopy, and Commd9 conditional knockout mice with cardiovascular phenotyping","pmids":["26553930"],"confidence":"High","gaps":["Did not identify the cargo-recognition adaptor (SNX17) for Notch","Why COMMD9/COMMD5 are specifically required versus other COMMDs unclear"]},{"year":2016,"claim":"Extended COMMD9's recycling role to LDLR and to cholesterol homeostasis, showing CCC cooperation with the WASH complex controls receptor fate and plasma lipids.","evidence":"Liver-specific Commd9 knockout mice, cholesterol measurements, LDLR localization, and LDL uptake assays","pmids":["26965651"],"confidence":"High","gaps":["Did not establish whether COMMD9 acts directly on LDLR or through complex integrity","Cargo-motif specificity not yet defined"]},{"year":2016,"claim":"Revealed a transcriptional arm of COMMD9 function distinct from endosomal recycling, mapping a direct COMM-domain interaction with TFDP1 that promotes E2F1 activity and cell-cycle progression.","evidence":"Co-IP with domain-deletion mapping, luciferase reporters, cell cycle and autophagy assays in NSCLC cells","pmids":["27871936"],"confidence":"Medium","gaps":["Single-lab evidence without in vivo confirmation","How COMMD9 partitions between cytoplasmic recycling and nuclear/transcriptional roles is unknown"]},{"year":2018,"claim":"Reframed COMMD9 as a structural keystone, showing its loss destabilizes the entire COMMD family and CCC core, explaining the pleiotropic receptor and disease phenotypes.","evidence":"Liver-specific Commd9 knockout mice with quantitative targeted proteomics, surface receptor quantification, and atherosclerosis assessment","pmids":["29545368"],"confidence":"High","gaps":["Did not resolve the assembly hierarchy or stoichiometry that makes COMMD9 essential for stability","Which phenotypes are direct versus secondary to complex collapse unclear"]},{"year":2021,"claim":"Tied COMMD9-dependent recycling to copper metabolism via ATP7B, while showing tissue-specific limits (enterocyte ATP7A regulation unaffected).","evidence":"Hepatocyte- and enterocyte-specific Commd9 knockout mice with tissue copper measurements, CCC component Western blotting, and ATP7B localization","pmids":["33262129"],"confidence":"Medium","gaps":["Basis for tissue-specific cargo dependence not defined","Direct ATP7B trafficking step not visualized at high resolution"]},{"year":2022,"claim":"Implicated COMMD9 in transcriptional repression by ETV6 in leukemia cells, broadening its transcription-regulatory associations.","evidence":"Genome-wide shRNA screen in pre-B ALL cells with validation of ETV6 target gene expression after COMMD9 knockdown","pmids":["35198911"],"confidence":"Low","gaps":["No biochemical binding or direct mechanism linking COMMD9 to ETV6","Effect may be indirect via complex-wide functions"]},{"year":2025,"claim":"Unified COMMD9's role under SNX17-dependent recycling and connected it to human disease, showing patient mutations disrupt Commander assembly and selectively reduce surface presentation of ΦxNPxY/F-motif cargo, causing Ritscher-Schinzel syndrome.","evidence":"Patient genetics, interactome co-IP, cell surface proteomics, and RSS mouse models with renal, skeletal, and neurological phenotypes","pmids":["40601774"],"confidence":"High","gaps":["Genotype-phenotype and tissue-specificity determinants of mutant cargo loss not fully resolved","Structural detail of how mutations impair assembly not defined"]},{"year":null,"claim":"How COMMD9 reconciles its cytoplasmic endosomal-recycling function with its nuclear transcriptional interactions (TFDP1/E2F1, ETV6) within a single regulatory framework remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the COMMD9 COMM domain within the assembled Commander complex","Mechanism partitioning COMMD9 between recycling and transcription unknown","Determinants of cargo and tissue selectivity undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]}],"complexes":["CCC (Commander) complex"],"partners":["COMMD5","CCDC22","CCDC93","C16ORF62","TFDP1","SNX17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P000","full_name":"COMM domain-containing protein 9","aliases":[],"length_aa":198,"mass_kda":21.8,"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":"Nucleus; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q9P000/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COMMD9","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"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":"COMMD2","stoichiometry":10.0},{"gene":"COMMD4","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COMMD9","total_profiled":1310},"omim":[{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"612377","title":"COMM DOMAIN-CONTAINING PROTEIN 6; COMMD6","url":"https://www.omim.org/entry/612377"},{"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"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COMMD9"},"hgnc":{"alias_symbol":["HSPC166","FLJ31106"],"prev_symbol":[]},"alphafold":{"accession":"Q9P000","domains":[{"cath_id":"-","chopping":"7-117","consensus_level":"high","plddt":86.6277,"start":7,"end":117},{"cath_id":"-","chopping":"123-198","consensus_level":"high","plddt":83.8326,"start":123,"end":198}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P000","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P000-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P000-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COMMD9","jax_strain_url":"https://www.jax.org/strain/search?query=COMMD9"},"sequence":{"accession":"Q9P000","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P000.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P000/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P000"}},"corpus_meta":[{"pmid":"26965651","id":"PMC_26965651","title":"CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26965651","citation_count":165,"is_preprint":false},{"pmid":"29545368","id":"PMC_29545368","title":"The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking.","date":"2018","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/29545368","citation_count":107,"is_preprint":false},{"pmid":"26553930","id":"PMC_26553930","title":"Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26553930","citation_count":54,"is_preprint":false},{"pmid":"27871936","id":"PMC_27871936","title":"COMMD9 promotes TFDP1/E2F1 transcriptional activity via interaction with TFDP1 in non-small cell lung cancer.","date":"2016","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/27871936","citation_count":51,"is_preprint":false},{"pmid":"33262129","id":"PMC_33262129","title":"Regulation of murine copper homeostasis by members of the COMMD protein family.","date":"2021","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/33262129","citation_count":33,"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":"37449204","id":"PMC_37449204","title":"Identification of biomarkers related to sepsis diagnosis based on bioinformatics and machine learning and experimental verification.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37449204","citation_count":12,"is_preprint":false},{"pmid":"20544419","id":"PMC_20544419","title":"Screening and identification of differentially expressed genes from chickens infected with Newcastle disease virus by suppression subtractive hybridization.","date":"2010","source":"Avian pathology : journal of the W.V.P.A","url":"https://pubmed.ncbi.nlm.nih.gov/20544419","citation_count":10,"is_preprint":false},{"pmid":"36758533","id":"PMC_36758533","title":"Whole-Exome Sequencing Indicated New Candidate Genes Associated with Unilateral Cryptorchidism in Pigs.","date":"2023","source":"Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36758533","citation_count":6,"is_preprint":false},{"pmid":"35198911","id":"PMC_35198911","title":"Identification of new ETV6 modulators through a high-throughput functional screening.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35198911","citation_count":6,"is_preprint":false},{"pmid":"40601774","id":"PMC_40601774","title":"Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40601774","citation_count":2,"is_preprint":false},{"pmid":"41339365","id":"PMC_41339365","title":"Whole-exome sequencing and burden analysis identify six novel candidate risk genes and expand the genetic landscape of Parkinson's disease.","date":"2025","source":"NPJ Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/41339365","citation_count":2,"is_preprint":false},{"pmid":"41173221","id":"PMC_41173221","title":"Study on the molecular mechanism of dietary FCE supplementation in regulating chicken meat quality.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41173221","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9034,"output_tokens":2218,"usd":0.030186,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9300,"output_tokens":3353,"usd":0.065162,"stage2_stop_reason":"end_turn"},"total_usd":0.095348,"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\": 2015,\n      \"finding\": \"COMMD9, together with its binding partner COMMD5, is specifically required within the CCC (COMMD-CCDC22-CCDC93) complex for endosomal recycling of Notch receptors to the cell surface; disruption of COMMD9 causes intracellular accumulation of Notch2 and reduced Notch signaling, while Commd9 deletion in mice causes embryonic lethality with cardiovascular defects bearing hallmarks of Notch deficiency.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, fluorescence microscopy of Notch2 trafficking, Commd9 conditional knockout mouse with phenotypic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, live-cell trafficking imaging, and in vivo genetic model with specific phenotypic readout across multiple orthogonal methods in one study\",\n      \"pmids\": [\"26553930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The CCC complex (containing COMMD9) and the WASH complex cooperate to mediate endosomal sorting of LDLR back to the cell surface; hepatic COMMD9 deficiency in mice leads to LDLR mislocalization, increased lysosomal degradation of LDLR, impaired LDL uptake, and elevated plasma LDL cholesterol levels.\",\n      \"method\": \"Liver-specific Commd9 knockout mice, plasma cholesterol measurements, LDLR localization by microscopy, LDL uptake assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo liver-specific KO with defined receptor trafficking and cholesterol phenotype, replicated across multiple COMMD family members and independent labs\",\n      \"pmids\": [\"26965651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COMMD9 interacts with TFDP1 (DP1) through its COMM domain; the DNA-binding domain of TFDP1 is required for this interaction; COMMD9 promotes TFDP1/E2F1 transcriptional activity, and COMMD9 knockdown attenuates TFDP1/E2F1 activation and enhances p53 signaling in NSCLC cells, arresting the cell cycle at G1/S.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mapping, siRNA knockdown with luciferase reporter assays, cell cycle analysis, and autophagy assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with domain mapping and functional reporter assays in a single lab, multiple orthogonal cellular readouts\",\n      \"pmids\": [\"27871936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COMMD9 (like COMMD1 and COMMD6) is required for the stability of the entire COMMD protein family and the core CCC complex (CCDC22, CCDC93, C16orf62); hepatic Commd9 knockout causes massive reduction in all 10 COMMD protein levels, destabilization of the CCC core, reduced cell-surface levels of LDLR and LRP1, hypercholesterolemia, and accelerated atherosclerosis.\",\n      \"method\": \"Liver-specific Commd9 knockout mice, quantitative targeted proteomics, Western blotting, cell surface receptor quantification, plasma lipid measurements, atherosclerosis assessment in ApoE3*Leiden mice\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with quantitative proteomics and multiple orthogonal functional readouts, independently confirmed across three COMMD family members\",\n      \"pmids\": [\"29545368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COMMD9 interacts with the epithelial sodium channel (ENaC) and reduces amiloride-sensitive current by decreasing ENaC cell surface expression; this effect is retained when COMMD1 is knocked down, indicating a COMMD1-independent mechanism.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiological current measurement (Ussing chamber), cell surface biotinylation, COMMD1 siRNA knockdown, immunofluorescence colocalization in renal collecting duct cells\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, functional current assay, and surface expression assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23637203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatic Commd9 deficiency (like Commd1 and Commd6 deficiency) causes destabilization of the entire CCC complex and leads to hepatic copper accumulation under high-copper diets, consistent with impaired ATP7B endosomal recycling; by contrast, enterocyte-specific Commd9 deficiency does not significantly alter ATP7A regulation or intestinal copper absorption.\",\n      \"method\": \"Hepatocyte-specific and enterocyte-specific Commd9 knockout mice, tissue copper level measurements, Western blotting for CCC complex components, ATP7B localization\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tissue-specific KO with biochemical and metal-level readouts, single lab\",\n      \"pmids\": [\"33262129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pathogenic mutations in COMMD9 (identified in Ritscher-Schinzel syndrome patients) disrupt Commander complex assembly; interactome analysis showed reduced binding of mutant COMMD9 to Commander subunits, and cell surface proteomics showed tissue-specific reduction in presentation of integral membrane proteins containing ΦxNPxY/F or ΦxNxxY/F sorting motifs recognized by SNX17, establishing COMMD9 as essential for SNX17-dependent endosomal recycling of multiple cargo proteins critical for kidney, bone, and brain development.\",\n      \"method\": \"Patient genetic analysis, interactome/co-immunoprecipitation assays, cell surface proteomics, mouse models of RSS with proteinuria, skeletal malformation, and neurological phenotypes\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — interactome analysis combined with cell surface proteomics, patient mutations, and in vivo mouse models with multiple orthogonal readouts in one study\",\n      \"pmids\": [\"40601774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing of COMMD9 abrogates ETV6 repressive transcriptional activity in pre-B acute lymphoblastic leukemia cells, identifying COMMD9 as a modulator of ETV6 function.\",\n      \"method\": \"Genome-wide shRNA screen in pre-B ALL cells followed by validation of ETV6 target gene expression upon COMMD9 knockdown\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional screen readout with limited mechanistic follow-up; no biochemical binding or pathway placement beyond reporter gene expression\",\n      \"pmids\": [\"35198911\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COMMD9 is an obligate subunit of the CCC (COMMD-CCDC22-CCDC93) Commander complex required for SNX17-dependent endosomal recycling of multiple cell-surface receptors including LDLR, LRP1, ATP7B, Notch2, and ENaC; it stabilizes the entire COMMD protein family and CCC core, and its loss causes receptor mislocalization, lysosomal degradation, hypercholesterolemia, copper accumulation, impaired Notch signaling, and—via patient mutations—Ritscher-Schinzel syndrome; additionally, COMMD9 promotes TFDP1/E2F1 transcriptional activity through a direct COMM-domain interaction with TFDP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COMMD9 is an obligate subunit of the CCC (COMMD-CCDC22-CCDC93) Commander complex that drives SNX17-dependent endosomal recycling of multiple cell-surface receptors, returning internalized cargo to the plasma membrane and preventing their lysosomal degradation [#1, #6]. It is structurally central to the system: hepatic loss of COMMD9 collapses the levels of the entire COMMD protein family and destabilizes the CCC core (CCDC22, CCDC93, C16orf62), establishing COMMD9 as a stability determinant for the whole assembly rather than a single-cargo adaptor [#3]. Through this recycling function it controls the surface presentation of cargo bearing SNX17-recognized ΦxNPxY/F sorting motifs, including LDLR and LRP1, so that COMMD9 deficiency causes receptor mislocalization, impaired LDL uptake, hypercholesterolemia, and accelerated atherosclerosis [#1, #3, #6]. The same machinery recycles ATP7B, and hepatic Commd9 loss produces copper accumulation under high-copper conditions [#5], and recycles Notch2, whose intracellular accumulation upon COMMD9 disruption reduces Notch signaling and underlies embryonic cardiovascular defects [#0]; COMMD9 also negatively regulates ENaC surface expression and amiloride-sensitive current through a COMMD1-independent mechanism [#4]. Pathogenic COMMD9 mutations that impair Commander assembly cause Ritscher-Schinzel syndrome with kidney, bone, and brain involvement [#6]. Beyond its endosomal role, COMMD9 interacts with TFDP1 via its COMM domain to promote TFDP1/E2F1 transcriptional activity, with its loss attenuating this output and enhancing p53 signaling to arrest the cell cycle at G1/S [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a discrete cellular consequence of COMMD9 action on a membrane channel, showing it limits ENaC surface expression independently of COMMD1 and hinting at a broader role in receptor surface regulation.\",\n      \"evidence\": \"Co-IP, Ussing chamber current measurement, surface biotinylation, and COMMD1 knockdown in renal collecting duct cells\",\n      \"pmids\": [\"23637203\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not place COMMD9 within the CCC complex or define the recycling step affecting ENaC\", \"Mechanism of COMMD1-independent action not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined COMMD9 as a CCC-complex factor required for recycling Notch receptors to the surface, linking its molecular trafficking role to an essential developmental signaling pathway in vivo.\",\n      \"evidence\": \"siRNA knockdown, co-IP, Notch2 trafficking microscopy, and Commd9 conditional knockout mice with cardiovascular phenotyping\",\n      \"pmids\": [\"26553930\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not identify the cargo-recognition adaptor (SNX17) for Notch\", \"Why COMMD9/COMMD5 are specifically required versus other COMMDs unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended COMMD9's recycling role to LDLR and to cholesterol homeostasis, showing CCC cooperation with the WASH complex controls receptor fate and plasma lipids.\",\n      \"evidence\": \"Liver-specific Commd9 knockout mice, cholesterol measurements, LDLR localization, and LDL uptake assays\",\n      \"pmids\": [\"26965651\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not establish whether COMMD9 acts directly on LDLR or through complex integrity\", \"Cargo-motif specificity not yet defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a transcriptional arm of COMMD9 function distinct from endosomal recycling, mapping a direct COMM-domain interaction with TFDP1 that promotes E2F1 activity and cell-cycle progression.\",\n      \"evidence\": \"Co-IP with domain-deletion mapping, luciferase reporters, cell cycle and autophagy assays in NSCLC cells\",\n      \"pmids\": [\"27871936\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single-lab evidence without in vivo confirmation\", \"How COMMD9 partitions between cytoplasmic recycling and nuclear/transcriptional roles is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reframed COMMD9 as a structural keystone, showing its loss destabilizes the entire COMMD family and CCC core, explaining the pleiotropic receptor and disease phenotypes.\",\n      \"evidence\": \"Liver-specific Commd9 knockout mice with quantitative targeted proteomics, surface receptor quantification, and atherosclerosis assessment\",\n      \"pmids\": [\"29545368\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not resolve the assembly hierarchy or stoichiometry that makes COMMD9 essential for stability\", \"Which phenotypes are direct versus secondary to complex collapse unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tied COMMD9-dependent recycling to copper metabolism via ATP7B, while showing tissue-specific limits (enterocyte ATP7A regulation unaffected).\",\n      \"evidence\": \"Hepatocyte- and enterocyte-specific Commd9 knockout mice with tissue copper measurements, CCC component Western blotting, and ATP7B localization\",\n      \"pmids\": [\"33262129\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Basis for tissue-specific cargo dependence not defined\", \"Direct ATP7B trafficking step not visualized at high resolution\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated COMMD9 in transcriptional repression by ETV6 in leukemia cells, broadening its transcription-regulatory associations.\",\n      \"evidence\": \"Genome-wide shRNA screen in pre-B ALL cells with validation of ETV6 target gene expression after COMMD9 knockdown\",\n      \"pmids\": [\"35198911\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No biochemical binding or direct mechanism linking COMMD9 to ETV6\", \"Effect may be indirect via complex-wide functions\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Unified COMMD9's role under SNX17-dependent recycling and connected it to human disease, showing patient mutations disrupt Commander assembly and selectively reduce surface presentation of ΦxNPxY/F-motif cargo, causing Ritscher-Schinzel syndrome.\",\n      \"evidence\": \"Patient genetics, interactome co-IP, cell surface proteomics, and RSS mouse models with renal, skeletal, and neurological phenotypes\",\n      \"pmids\": [\"40601774\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Genotype-phenotype and tissue-specificity determinants of mutant cargo loss not fully resolved\", \"Structural detail of how mutations impair assembly not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COMMD9 reconciles its cytoplasmic endosomal-recycling function with its nuclear transcriptional interactions (TFDP1/E2F1, ETV6) within a single regulatory framework remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the COMMD9 COMM domain within the assembled Commander complex\", \"Mechanism partitioning COMMD9 between recycling and transcription unknown\", \"Determinants of cargo and tissue selectivity undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"CCC (Commander) complex\"],\n    \"partners\": [\"COMMD5\", \"CCDC22\", \"CCDC93\", \"C16orf62\", \"TFDP1\", \"SNX17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}