{"gene":"CCDC93","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2014,"finding":"CCDC93, together with CCDC22 and C16orf62, forms the CCC (COMMD/CCDC22/CCDC93) complex that localizes to early endosomes and interacts with the WASH complex to regulate endosomal trafficking of the copper transporter ATP7A; the carboxyl-terminal end of CCDC93 interacts with FAM21 (a WASH complex subunit) to recruit the CCC complex to endosomes.","method":"Co-immunoprecipitation, protein depletion (siRNA knockdown), endosomal localization assays, copper homeostasis functional readouts","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying complex composition and specific interaction domain, combined with loss-of-function phenotype (ATP7A mislocalization, copper accumulation), single lab but multiple orthogonal methods","pmids":["25355947"],"is_preprint":false},{"year":2017,"finding":"CCDC93 is a core subunit of the CCC complex (CCDC93, CCDC22, COMMD proteins), which associates with the cargo adaptor SNX17 and the Retriever complex to form a larger assembly that prevents lysosomal degradation and promotes cell surface recycling of α5β1 integrin and over 120 other cell surface proteins.","method":"Quantitative proteomics, Co-immunoprecipitation, cell surface proteomics, loss-of-function depletion with cargo recycling readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (quantitative proteomics, Co-IP, surface proteomics), independently built upon by subsequent papers","pmids":["28892079"],"is_preprint":false},{"year":2016,"finding":"The CCC complex (including CCDC93) is required for endosomal sorting and recycling of LDLR back to the cell surface; depletion of CCC components leads to LDLR mislocalization and decreased LDL uptake.","method":"Liver-specific knockout mice, CRISPR/Cas9 somatic gene editing, plasma LDL measurements, LDLR localization assays, LDL uptake assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models (KO mice), cellular loss-of-function with defined molecular phenotype, replicated across multiple COMMD/CCC components","pmids":["26965651"],"is_preprint":false},{"year":2015,"finding":"The CCC complex (including CCDC93) controls Notch receptor recycling to the cell surface; disruption of the CCC complex causes intracellular accumulation of Notch2 and reduced Notch signaling.","method":"siRNA depletion of CCC components, Notch2 localization assays, Notch signaling reporter assays, conditional Commd9 knockout mice","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined signaling phenotype, in vivo mouse model corroborating cellular findings, multiple CCC components tested","pmids":["26553930"],"is_preprint":false},{"year":2019,"finding":"The CCC complex (including CCDC93) maintains normal endosomal levels of phosphatidylinositol-3-phosphate (PI(3)P) by regulating the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2; CCC depletion elevates endosomal PI(3)P, leading to enhanced WASH recruitment, excess endosomal F-actin, and trapping of internalized receptors.","method":"siRNA depletion of CCC components, PI(3)P biosensor imaging, F-actin quantification, MTMR2 phosphorylation and localization assays, receptor recycling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (lipid biosensors, actin imaging, phosphatase recruitment assays) in a single study establishing a mechanistic pathway","pmids":["31537807"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of the Retriever complex was determined, and biochemical, cellular, and proteomic analyses revealed the structural organization of the entire Retriever-CCC complex; CCDC93 (along with CCDC22) scaffolds the CCC and Retriever subcomplexes together; cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis.","method":"Cryogenic electron microscopy, AlphaFold structural predictions, biochemical pulldowns, cellular and proteomic analyses, mutagenesis of disease variants","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure combined with mutagenesis and proteomic validation; also corroborated by independent preprint/Research Square version","pmids":["38062209","37397996","37333304"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the endogenous human Commander complex shows that CCDC22 and CCDC93 act as a scaffold bridging the stable COMMD1-10 core and the effector module containing DENND10 and Retriever (VPS26C, VPS29, VPS35L); key interaction interfaces between these submodules were identified.","method":"Cryogenic electron microscopy, mass spectrometry-based proteomics, structural analysis of endogenous complex","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure of endogenous complex with MS-based validation of composition; single study but rigorous structural approach","pmids":["38459129"],"is_preprint":false},{"year":2013,"finding":"CCDC93 (along with CCDC22 and related proteins) contains a divergent N-terminal calponin homology (NN-CH)-like domain adjoined to C-terminal heptad repeats predicted to form a coiled-coil, defining a novel protein family sharing evolutionary ancestry with NDC80/NUF2 kinetochore components.","method":"Computational profile-to-profile comparisons, structure modeling","journal":"Bioinformatics (Oxford, England)","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of domain function","pmids":["24257188"],"is_preprint":false},{"year":2018,"finding":"COMMD protein deficiency destabilizes the core of the CCC complex (CCDC22 and CCDC93 protein levels are reduced), and CCDC22 deletion by CRISPR/Cas9 likewise destabilizes the complete CCC complex, demonstrating that the integrity of COMMD proteins is required for CCC complex stability.","method":"Liver-specific Commd knockout mice, quantitative targeted proteomics, CRISPR/Cas9 somatic Ccdc22 deletion, western blotting of complex components","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models across multiple COMMD genes all showing same effect on CCDC93/CCDC22 stability, replicated across multiple mouse models","pmids":["29545368"],"is_preprint":false},{"year":2020,"finding":"A coding variant in CCDC93 (p.Pro228Leu) increases CCDC93 protein stability; overexpression of CCDC93 in mice decreases plasma LDL-c, while CCDC93 ablation reduces LDLR cell surface levels and LDL uptake.","method":"Population genetics combined with functional cell-based assays (overexpression in mice, CCDC93 ablation), LDLR surface level and LDL uptake assays","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined mouse overexpression and cellular knockdown with defined molecular phenotype, single lab","pmids":["31630160"],"is_preprint":false},{"year":2021,"finding":"Deficiency of any of three COMMD genes (Commd1, Commd6, or Commd9) destabilizes the entire CCC complex including CCDC93, and the CCC complex regulates ATP7B endosomal recycling and copper excretion in hepatocytes.","method":"Enterocyte- and hepatocyte-specific COMMD knockout mice, biochemical analysis of CCC complex integrity, copper level measurements","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic mouse models with biochemical measurement of CCC complex levels, single lab","pmids":["33262129"],"is_preprint":false},{"year":2025,"finding":"The CCC complex (including CCDC93) is essential for phagosome maturation in macrophages; CCC deficiency impairs phagosome-lysosome fusion, leads to excessive PI(3)P accumulation on phagosome membranes, and reduces bacterial clearance.","method":"Bone marrow-derived macrophage (BMDM) loss-of-function, PI(3)P imaging, phagosome-lysosome fusion assays, bacterial clearance assays","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (PI(3)P, fusion, killing), preprint not yet peer-reviewed","pmids":["41473320"],"is_preprint":true},{"year":2025,"finding":"CCDC93 interacts with WIPI2 (a PROPPIN protein) as part of the CROP2 complex (Retriever-PROPPIN complex), which is required for endosomal exit of β1-Integrin but not for CROP (Retromer-WIPI1)-dependent cargos such as EGFR or GLUT1; WIPI2 uses an FSSS motif to integrate into the Retriever complex via interaction with CCDC93.","method":"Co-immunoprecipitation, cargo trafficking assays (β1-Integrin, EGFR, GLUT1), mutagenesis of FSSS motif, loss-of-function depletion","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping with mutational validation and pathway-selective cargo assays; preprint only","pmids":["bio_10.1101_2025.10.08.681146"],"is_preprint":true},{"year":2025,"finding":"Mutations in CCDC93 cause Ritscher-Schinzel syndrome (RSS) by disrupting Commander complex assembly, leading to reduced cell surface presentation of integral membrane proteins containing SNX17-recognized ΦxNPxY/F sorting motifs; mouse models of CCDC93 deficiency replicate RSS phenotypes including proteinuria, skeletal malformation, and neurological impairment.","method":"Interactome analysis of patient mutations, cell surface proteomics, mouse models of CCDC93 deficiency, motif analysis of cargo proteins","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics combined with interactome/proteomic analyses and mouse models, multiple orthogonal approaches establishing mechanistic basis of disease","pmids":["40601774"],"is_preprint":false},{"year":2025,"finding":"CCDC22 mutations (p.E208K and p.P172R) that impair CCC complex assembly do so by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding, demonstrating that COMMD binding to CCDC22 is required for CCC complex integrity; CCDC93 remains part of the complex that is disrupted by these mutations.","method":"Mutagenesis of CCDC22, co-immunoprecipitation of CCC complex components including CCDC93, patient mutation characterization","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP-based complex assembly assay with defined interaction surface, but primarily focused on CCDC22 interaction; CCDC93 involvement inferred as part of the disrupted CCC complex","pmids":["40448120"],"is_preprint":false},{"year":2024,"finding":"Heterozygous Ccdc93 deletion in mice (homozygous deletion is embryonic lethal by day 10.5) results in elevated systolic blood pressure, impaired acetylcholine-induced arterial relaxation, enhanced phenylephrine-induced contraction, elevated plasma free fatty acids, and aortic mitochondrial dysfunction with aberrant Parkin and Nix expression.","method":"CRISPR/Cas9 Ccdc93 knockout mice, wire myography, RNA-Seq transcriptome analysis, plasma fatty acid measurements, western blotting for mitochondrial proteins","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic mouse model with multiple functional readouts; novel vascular/mitochondrial role not previously established, single lab","pmids":["39250516"],"is_preprint":false},{"year":2025,"finding":"Loss of COMMD3 (a CCC complex component) increases release of lysosomal proteins through extracellular vesicles, leading to impaired delivery to endolysosomes and lysosomal dysfunction; COMMD3 was identified as a modifier of lysosomal glucocerebrosidase (GCase) activity through a genome-wide CRISPR interference screen.","method":"Pooled genome-wide CRISPRi screen, extracellular vesicle proteomics, lysosomal function assays","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen with mechanistic follow-up (EV proteomics, lysosomal assays), but CCDC93 involvement is as a complex component context rather than direct subject of study","pmids":["40209002"],"is_preprint":false}],"current_model":"CCDC93 is a core scaffolding subunit of the evolutionarily conserved CCC (COMMD/CCDC22/CCDC93) complex that, together with Retriever (VPS35L/VPS26C/VPS29) and the WASH complex, forms the larger Commander assembly; structural studies show CCDC93 (with CCDC22) bridges the COMMD1-10 core to the Retriever subcomplex, and the CCC complex functions mechanistically by regulating endosomal PI(3)P levels through the phosphatase MTMR2 and by coupling to WASH-mediated actin polymerization, thereby directing SNX17-dependent recycling of hundreds of plasma membrane proteins—including integrins, LDLR, ATP7A/B, Notch receptors, and HER2—from endosomes back to the cell surface, while also controlling phagosome maturation and lysosomal function in immune cells."},"narrative":{"mechanistic_narrative":"CCDC93 is a core scaffolding subunit of the endosomal CCC (COMMD/CCDC22/CCDC93) complex that directs the recycling of internalized plasma membrane proteins back to the cell surface and prevents their lysosomal degradation [PMID:25355947, PMID:28892079]. Together with CCDC22, it forms the structural scaffold that bridges the stable COMMD1-10 core to the Retriever subcomplex (VPS35L/VPS26C/VPS29) and the effector DENND10, assembling the larger Commander complex [PMID:38062209, PMID:37397996, PMID:37333304, PMID:38459129]; complex integrity depends reciprocally on COMMD proteins, whose loss destabilizes CCDC93 and CCDC22 [PMID:29545368, PMID:33262129]. CCDC93 is recruited to early endosomes through its carboxyl-terminal interaction with the WASH subunit FAM21, coupling cargo sorting to actin polymerization [PMID:25355947]. Mechanistically, the complex maintains endosomal phosphatidylinositol-3-phosphate homeostasis by controlling phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2; its loss elevates PI(3)P, drives excess WASH-dependent F-actin, and traps internalized receptors [PMID:31537807]. Acting with the cargo adaptor SNX17, the complex recycles α5β1 integrin, LDLR, ATP7A/B, and Notch2 along with over a hundred surface proteins bearing ΦxNPxY/F sorting motifs [PMID:28892079, PMID:26965651, PMID:26553930, PMID:40601774], and CCDC93 also engages the PROPPIN protein WIPI2 to support a distinct β1-integrin recycling route [PMID:bio_10.1101_2025.10.08.681146]. CCDC93 thereby supports physiological copper excretion, LDL clearance, and Notch signaling [PMID:25355947, PMID:26965651, PMID:26553930], and in macrophages the complex is required for phagosome maturation and bacterial clearance [PMID:41473320]. Loss-of-function mutations in CCDC93 cause Ritscher-Schinzel syndrome by disrupting Commander assembly and reducing surface presentation of SNX17 cargoes, phenocopied in mouse models displaying proteinuria, skeletal, and neurological defects [PMID:40601774].","teleology":[{"year":2014,"claim":"Established CCDC93 as a constituent of the CCC complex and defined how it is targeted to endosomes, answering what molecular machine it belongs to and how that machine localizes.","evidence":"Reciprocal Co-IP, siRNA depletion, and copper homeostasis readouts mapping the CCDC93 C-terminal interaction with FAM21","pmids":["25355947"],"confidence":"High","gaps":["Did not resolve atomic architecture of CCDC93 within the complex","Cargo repertoire beyond ATP7A not yet defined"]},{"year":2015,"claim":"Showed the CCC complex governs surface recycling of signaling receptors, extending its role from a single transporter to broad receptor homeostasis.","evidence":"siRNA depletion, Notch2 localization and reporter assays, conditional Commd9 knockout mice","pmids":["26553930"],"confidence":"High","gaps":["Direct CCDC93 contribution distinct from other subunits not isolated","Sorting-motif requirement on Notch2 not defined"]},{"year":2016,"claim":"Demonstrated in vivo that CCC-dependent recycling controls LDLR surface levels and plasma lipid handling, linking the complex to systemic physiology.","evidence":"Liver-specific knockout mice, CRISPR somatic editing, LDL uptake and LDLR localization assays","pmids":["26965651"],"confidence":"High","gaps":["CCDC93-specific knockout not used here","Mechanism of LDLR retrieval step unresolved"]},{"year":2017,"claim":"Defined the CCC complex as the lysosomal-degradation-protecting partner of SNX17 and Retriever, establishing the scope of cargo it recycles.","evidence":"Quantitative cell-surface proteomics, Co-IP, and loss-of-function recycling assays across >120 cargoes","pmids":["28892079"],"confidence":"High","gaps":["How CCDC93 physically couples to SNX17/Retriever not yet structurally resolved","Selectivity rules for cargo unclear"]},{"year":2018,"claim":"Showed CCC complex integrity is interdependent, with COMMD proteins required to stabilize CCDC93 and CCDC22, clarifying assembly hierarchy.","evidence":"Liver-specific Commd knockout mice, targeted proteomics, CRISPR Ccdc22 deletion, western blotting","pmids":["29545368"],"confidence":"High","gaps":["Order of complex assembly not defined","Whether CCDC93 has roles outside the assembled complex unknown"]},{"year":2019,"claim":"Provided the lipid-level mechanism by which the complex acts, linking CCDC93/CCC to MTMR2-controlled endosomal PI(3)P and WASH-dependent actin.","evidence":"siRNA depletion with PI(3)P biosensors, F-actin quantification, and MTMR2 phosphorylation/recruitment assays","pmids":["31537807"],"confidence":"High","gaps":["Direct enzymatic relationship between CCDC93 and MTMR2 not established","Kinase responsible for MTMR2 phosphorylation not identified"]},{"year":2020,"claim":"Connected human genetic variation in CCDC93 to LDL handling, showing CCDC93 dosage and stability directly tune LDLR surface levels.","evidence":"Population genetics with mouse overexpression and cellular ablation, LDLR surface and LDL uptake assays","pmids":["31630160"],"confidence":"Medium","gaps":["Single-lab functional validation","Mechanism by which p.Pro228Leu stabilizes protein not resolved"]},{"year":2021,"claim":"Confirmed across multiple COMMD genes that the assembled complex including CCDC93 drives hepatic ATP7B recycling and copper excretion.","evidence":"Tissue-specific COMMD knockout mice, biochemical CCC integrity analysis, copper measurements","pmids":["33262129"],"confidence":"Medium","gaps":["CCDC93-specific deletion not tested","Single lab"]},{"year":2023,"claim":"Resolved the structural basis of CCDC93's scaffolding role, showing it bridges the COMMD core to Retriever and that cancer mutations break this coupling.","evidence":"Cryo-EM of Retriever, AlphaFold modeling, biochemical pulldowns, proteomics, disease-variant mutagenesis","pmids":["38062209","37397996","37333304"],"confidence":"High","gaps":["Conformational dynamics during cargo handoff not captured","Membrane-bound state not resolved"]},{"year":2024,"claim":"Determined the endogenous Commander architecture, placing CCDC22-CCDC93 as the scaffold linking the COMMD core to DENND10 and Retriever effector module.","evidence":"Cryo-EM of endogenous human Commander with MS-based composition validation","pmids":["38459129"],"confidence":"High","gaps":["Function of DENND10 module within recycling not defined","Dynamics of submodule engagement unresolved"]},{"year":2024,"claim":"Revealed a vascular and mitochondrial requirement for CCDC93 in vivo, indicating phenotypes beyond cargo recycling and that the gene is developmentally essential.","evidence":"CRISPR Ccdc93 knockout mice (homozygous lethal), wire myography, RNA-Seq, plasma fatty acid and mitochondrial protein analysis","pmids":["39250516"],"confidence":"Medium","gaps":["Mechanistic link between recycling defects and mitochondrial dysfunction unclear","Single lab"]},{"year":2025,"claim":"Established CCDC93 as a Ritscher-Schinzel syndrome gene, mechanistically tying disease to disrupted Commander assembly and loss of SNX17-motif cargo at the surface.","evidence":"Patient mutation interactome analysis, cell-surface proteomics, CCDC93-deficient mouse models, cargo motif analysis","pmids":["40601774"],"confidence":"High","gaps":["Tissue-specific basis of individual RSS features not dissected","Relationship to vascular/mitochondrial phenotypes not integrated"]},{"year":2025,"claim":"Identified WIPI2 as a CCDC93 partner defining a pathway-selective recycling route, refining how distinct cargo classes are sorted.","evidence":"Co-IP, FSSS-motif mutagenesis, and selective cargo trafficking assays (β1-integrin vs EGFR/GLUT1) (preprint)","pmids":["bio_10.1101_2025.10.08.681146"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Structural basis of WIPI2-CCDC93 interface not resolved"]},{"year":2025,"claim":"Extended CCC function to innate immunity, showing the complex is required for phagosome maturation and bacterial clearance via PI(3)P control.","evidence":"BMDM loss-of-function, phagosomal PI(3)P imaging, phagosome-lysosome fusion and bacterial clearance assays (preprint)","pmids":["41473320"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Whether CCDC93 acts identically on phagosomes and endosomes unverified"]},{"year":null,"claim":"How the broader CCDC93-dependent phenotypes (vascular tone, mitochondrial homeostasis, lysosomal secretion) mechanistically derive from endosomal recycling defects remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model connecting recycling defects to mitochondrial/vascular phenotypes","Cargo-by-cargo selectivity rules of the complex not fully defined","Membrane-engaged structural state of CCDC93 not captured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5,6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,13]}],"complexes":["CCC complex","Commander complex","Retriever-CCC complex"],"partners":["CCDC22","FAM21","SNX17","MTMR2","WIPI2","COMMD1","VPS35L","DENND10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q567U6","full_name":"Coiled-coil domain-containing protein 93","aliases":[],"length_aa":631,"mass_kda":73.2,"function":"Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex (PubMed:37172566, PubMed:38459129). Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels (PubMed:37172566, PubMed:38459129). The CCC complex associates with SNX17, retriever and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGA5:ITGB1 (PubMed:25355947, PubMed:28892079). Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes and is dependent on its interaction with WASHC2C (PubMed:25355947) (Microbial infection) The CCC complex, in collaboration with the heterotrimeric retriever complex, mediates the exit of human papillomavirus to the cell surface","subcellular_location":"Early endosome","url":"https://www.uniprot.org/uniprotkb/Q567U6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC93","classification":"Not Classified","n_dependent_lines":105,"n_total_lines":1208,"dependency_fraction":0.0869205298013245},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000125633","cell_line_id":"CID000263","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CCDC22","stoichiometry":10.0},{"gene":"C16ORF62","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":10.0},{"gene":"COMMD1","stoichiometry":10.0},{"gene":"FAM45A;FAM45B","stoichiometry":10.0},{"gene":"COMMD2","stoichiometry":10.0},{"gene":"COMMD9","stoichiometry":10.0},{"gene":"COMMD8","stoichiometry":10.0},{"gene":"COMMD10","stoichiometry":10.0},{"gene":"COMMD5","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000263","total_profiled":1310},"omim":[{"mim_id":"620553","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 93; CCDC93","url":"https://www.omim.org/entry/620553"},{"mim_id":"618981","title":"VPS35 ENDOSOMAL PROTEIN-SORTING FACTOR-LIKE; VPS35L","url":"https://www.omim.org/entry/618981"},{"mim_id":"613632","title":"WASH COMPLEX, SUBUNIT 1; WASHC1","url":"https://www.omim.org/entry/613632"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC93"},"hgnc":{"alias_symbol":["FLJ10996"],"prev_symbol":[]},"alphafold":{"accession":"Q567U6","domains":[{"cath_id":"1.10.418","chopping":"22-151","consensus_level":"high","plddt":84.1552,"start":22,"end":151},{"cath_id":"1.20.5","chopping":"316-377","consensus_level":"medium","plddt":85.8784,"start":316,"end":377},{"cath_id":"1.20.5","chopping":"378-424","consensus_level":"medium","plddt":87.4291,"start":378,"end":424}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q567U6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q567U6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q567U6-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC93","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC93"},"sequence":{"accession":"Q567U6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q567U6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q567U6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q567U6"}},"corpus_meta":[{"pmid":"28892079","id":"PMC_28892079","title":"Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling.","date":"2017","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28892079","citation_count":282,"is_preprint":false},{"pmid":"25355947","id":"PMC_25355947","title":"COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25355947","citation_count":186,"is_preprint":false},{"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":"30993794","id":"PMC_30993794","title":"Towards a molecular understanding of endosomal trafficking by Retromer and Retriever.","date":"2019","source":"Traffic (Copenhagen, 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complex to endosomes.\",\n      \"method\": \"Co-immunoprecipitation, protein depletion (siRNA knockdown), endosomal localization assays, copper homeostasis functional readouts\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying complex composition and specific interaction domain, combined with loss-of-function phenotype (ATP7A mislocalization, copper accumulation), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25355947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCDC93 is a core subunit of the CCC complex (CCDC93, CCDC22, COMMD proteins), which associates with the cargo adaptor SNX17 and the Retriever complex to form a larger assembly that prevents lysosomal degradation and promotes cell surface recycling of α5β1 integrin and over 120 other cell surface proteins.\",\n      \"method\": \"Quantitative proteomics, Co-immunoprecipitation, cell surface proteomics, loss-of-function depletion with cargo recycling readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (quantitative proteomics, Co-IP, surface proteomics), independently built upon by subsequent papers\",\n      \"pmids\": [\"28892079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The CCC complex (including CCDC93) is required for endosomal sorting and recycling of LDLR back to the cell surface; depletion of CCC components leads to LDLR mislocalization and decreased LDL uptake.\",\n      \"method\": \"Liver-specific knockout mice, CRISPR/Cas9 somatic gene editing, plasma LDL measurements, LDLR localization assays, LDL uptake assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models (KO mice), cellular loss-of-function with defined molecular phenotype, replicated across multiple COMMD/CCC components\",\n      \"pmids\": [\"26965651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The CCC complex (including CCDC93) controls Notch receptor recycling to the cell surface; disruption of the CCC complex causes intracellular accumulation of Notch2 and reduced Notch signaling.\",\n      \"method\": \"siRNA depletion of CCC components, Notch2 localization assays, Notch signaling reporter assays, conditional Commd9 knockout mice\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined signaling phenotype, in vivo mouse model corroborating cellular findings, multiple CCC components tested\",\n      \"pmids\": [\"26553930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CCC complex (including CCDC93) maintains normal endosomal levels of phosphatidylinositol-3-phosphate (PI(3)P) by regulating the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2; CCC depletion elevates endosomal PI(3)P, leading to enhanced WASH recruitment, excess endosomal F-actin, and trapping of internalized receptors.\",\n      \"method\": \"siRNA depletion of CCC components, PI(3)P biosensor imaging, F-actin quantification, MTMR2 phosphorylation and localization assays, receptor recycling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (lipid biosensors, actin imaging, phosphatase recruitment assays) in a single study establishing a mechanistic pathway\",\n      \"pmids\": [\"31537807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of the Retriever complex was determined, and biochemical, cellular, and proteomic analyses revealed the structural organization of the entire Retriever-CCC complex; CCDC93 (along with CCDC22) scaffolds the CCC and Retriever subcomplexes together; cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis.\",\n      \"method\": \"Cryogenic electron microscopy, AlphaFold structural predictions, biochemical pulldowns, cellular and proteomic analyses, mutagenesis of disease variants\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure combined with mutagenesis and proteomic validation; also corroborated by independent preprint/Research Square version\",\n      \"pmids\": [\"38062209\", \"37397996\", \"37333304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the endogenous human Commander complex shows that CCDC22 and CCDC93 act as a scaffold bridging the stable COMMD1-10 core and the effector module containing DENND10 and Retriever (VPS26C, VPS29, VPS35L); key interaction interfaces between these submodules were identified.\",\n      \"method\": \"Cryogenic electron microscopy, mass spectrometry-based proteomics, structural analysis of endogenous complex\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure of endogenous complex with MS-based validation of composition; single study but rigorous structural approach\",\n      \"pmids\": [\"38459129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCDC93 (along with CCDC22 and related proteins) contains a divergent N-terminal calponin homology (NN-CH)-like domain adjoined to C-terminal heptad repeats predicted to form a coiled-coil, defining a novel protein family sharing evolutionary ancestry with NDC80/NUF2 kinetochore components.\",\n      \"method\": \"Computational profile-to-profile comparisons, structure modeling\",\n      \"journal\": \"Bioinformatics (Oxford, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of domain function\",\n      \"pmids\": [\"24257188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COMMD protein deficiency destabilizes the core of the CCC complex (CCDC22 and CCDC93 protein levels are reduced), and CCDC22 deletion by CRISPR/Cas9 likewise destabilizes the complete CCC complex, demonstrating that the integrity of COMMD proteins is required for CCC complex stability.\",\n      \"method\": \"Liver-specific Commd knockout mice, quantitative targeted proteomics, CRISPR/Cas9 somatic Ccdc22 deletion, western blotting of complex components\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models across multiple COMMD genes all showing same effect on CCDC93/CCDC22 stability, replicated across multiple mouse models\",\n      \"pmids\": [\"29545368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A coding variant in CCDC93 (p.Pro228Leu) increases CCDC93 protein stability; overexpression of CCDC93 in mice decreases plasma LDL-c, while CCDC93 ablation reduces LDLR cell surface levels and LDL uptake.\",\n      \"method\": \"Population genetics combined with functional cell-based assays (overexpression in mice, CCDC93 ablation), LDLR surface level and LDL uptake assays\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined mouse overexpression and cellular knockdown with defined molecular phenotype, single lab\",\n      \"pmids\": [\"31630160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Deficiency of any of three COMMD genes (Commd1, Commd6, or Commd9) destabilizes the entire CCC complex including CCDC93, and the CCC complex regulates ATP7B endosomal recycling and copper excretion in hepatocytes.\",\n      \"method\": \"Enterocyte- and hepatocyte-specific COMMD knockout mice, biochemical analysis of CCC complex integrity, copper level measurements\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic mouse models with biochemical measurement of CCC complex levels, single lab\",\n      \"pmids\": [\"33262129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CCC complex (including CCDC93) is essential for phagosome maturation in macrophages; CCC deficiency impairs phagosome-lysosome fusion, leads to excessive PI(3)P accumulation on phagosome membranes, and reduces bacterial clearance.\",\n      \"method\": \"Bone marrow-derived macrophage (BMDM) loss-of-function, PI(3)P imaging, phagosome-lysosome fusion assays, bacterial clearance assays\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (PI(3)P, fusion, killing), preprint not yet peer-reviewed\",\n      \"pmids\": [\"41473320\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC93 interacts with WIPI2 (a PROPPIN protein) as part of the CROP2 complex (Retriever-PROPPIN complex), which is required for endosomal exit of β1-Integrin but not for CROP (Retromer-WIPI1)-dependent cargos such as EGFR or GLUT1; WIPI2 uses an FSSS motif to integrate into the Retriever complex via interaction with CCDC93.\",\n      \"method\": \"Co-immunoprecipitation, cargo trafficking assays (β1-Integrin, EGFR, GLUT1), mutagenesis of FSSS motif, loss-of-function depletion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping with mutational validation and pathway-selective cargo assays; preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.10.08.681146\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mutations in CCDC93 cause Ritscher-Schinzel syndrome (RSS) by disrupting Commander complex assembly, leading to reduced cell surface presentation of integral membrane proteins containing SNX17-recognized ΦxNPxY/F sorting motifs; mouse models of CCDC93 deficiency replicate RSS phenotypes including proteinuria, skeletal malformation, and neurological impairment.\",\n      \"method\": \"Interactome analysis of patient mutations, cell surface proteomics, mouse models of CCDC93 deficiency, motif analysis of cargo proteins\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics combined with interactome/proteomic analyses and mouse models, multiple orthogonal approaches establishing mechanistic basis of disease\",\n      \"pmids\": [\"40601774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC22 mutations (p.E208K and p.P172R) that impair CCC complex assembly do so by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding, demonstrating that COMMD binding to CCDC22 is required for CCC complex integrity; CCDC93 remains part of the complex that is disrupted by these mutations.\",\n      \"method\": \"Mutagenesis of CCDC22, co-immunoprecipitation of CCC complex components including CCDC93, patient mutation characterization\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP-based complex assembly assay with defined interaction surface, but primarily focused on CCDC22 interaction; CCDC93 involvement inferred as part of the disrupted CCC complex\",\n      \"pmids\": [\"40448120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Heterozygous Ccdc93 deletion in mice (homozygous deletion is embryonic lethal by day 10.5) results in elevated systolic blood pressure, impaired acetylcholine-induced arterial relaxation, enhanced phenylephrine-induced contraction, elevated plasma free fatty acids, and aortic mitochondrial dysfunction with aberrant Parkin and Nix expression.\",\n      \"method\": \"CRISPR/Cas9 Ccdc93 knockout mice, wire myography, RNA-Seq transcriptome analysis, plasma fatty acid measurements, western blotting for mitochondrial proteins\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic mouse model with multiple functional readouts; novel vascular/mitochondrial role not previously established, single lab\",\n      \"pmids\": [\"39250516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of COMMD3 (a CCC complex component) increases release of lysosomal proteins through extracellular vesicles, leading to impaired delivery to endolysosomes and lysosomal dysfunction; COMMD3 was identified as a modifier of lysosomal glucocerebrosidase (GCase) activity through a genome-wide CRISPR interference screen.\",\n      \"method\": \"Pooled genome-wide CRISPRi screen, extracellular vesicle proteomics, lysosomal function assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen with mechanistic follow-up (EV proteomics, lysosomal assays), but CCDC93 involvement is as a complex component context rather than direct subject of study\",\n      \"pmids\": [\"40209002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC93 is a core scaffolding subunit of the evolutionarily conserved CCC (COMMD/CCDC22/CCDC93) complex that, together with Retriever (VPS35L/VPS26C/VPS29) and the WASH complex, forms the larger Commander assembly; structural studies show CCDC93 (with CCDC22) bridges the COMMD1-10 core to the Retriever subcomplex, and the CCC complex functions mechanistically by regulating endosomal PI(3)P levels through the phosphatase MTMR2 and by coupling to WASH-mediated actin polymerization, thereby directing SNX17-dependent recycling of hundreds of plasma membrane proteins—including integrins, LDLR, ATP7A/B, Notch receptors, and HER2—from endosomes back to the cell surface, while also controlling phagosome maturation and lysosomal function in immune cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCDC93 is a core scaffolding subunit of the endosomal CCC (COMMD/CCDC22/CCDC93) complex that directs the recycling of internalized plasma membrane proteins back to the cell surface and prevents their lysosomal degradation [#0, #1]. Together with CCDC22, it forms the structural scaffold that bridges the stable COMMD1-10 core to the Retriever subcomplex (VPS35L/VPS26C/VPS29) and the effector DENND10, assembling the larger Commander complex [#5, #6]; complex integrity depends reciprocally on COMMD proteins, whose loss destabilizes CCDC93 and CCDC22 [#8, #10]. CCDC93 is recruited to early endosomes through its carboxyl-terminal interaction with the WASH subunit FAM21, coupling cargo sorting to actin polymerization [#0]. Mechanistically, the complex maintains endosomal phosphatidylinositol-3-phosphate homeostasis by controlling phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2; its loss elevates PI(3)P, drives excess WASH-dependent F-actin, and traps internalized receptors [#4]. Acting with the cargo adaptor SNX17, the complex recycles α5β1 integrin, LDLR, ATP7A/B, and Notch2 along with over a hundred surface proteins bearing ΦxNPxY/F sorting motifs [#1, #2, #3, #13], and CCDC93 also engages the PROPPIN protein WIPI2 to support a distinct β1-integrin recycling route [#12]. CCDC93 thereby supports physiological copper excretion, LDL clearance, and Notch signaling [#0, #2, #3], and in macrophages the complex is required for phagosome maturation and bacterial clearance [#11]. Loss-of-function mutations in CCDC93 cause Ritscher-Schinzel syndrome by disrupting Commander assembly and reducing surface presentation of SNX17 cargoes, phenocopied in mouse models displaying proteinuria, skeletal, and neurological defects [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established CCDC93 as a constituent of the CCC complex and defined how it is targeted to endosomes, answering what molecular machine it belongs to and how that machine localizes.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion, and copper homeostasis readouts mapping the CCDC93 C-terminal interaction with FAM21\",\n      \"pmids\": [\"25355947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic architecture of CCDC93 within the complex\", \"Cargo repertoire beyond ATP7A not yet defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed the CCC complex governs surface recycling of signaling receptors, extending its role from a single transporter to broad receptor homeostasis.\",\n      \"evidence\": \"siRNA depletion, Notch2 localization and reporter assays, conditional Commd9 knockout mice\",\n      \"pmids\": [\"26553930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CCDC93 contribution distinct from other subunits not isolated\", \"Sorting-motif requirement on Notch2 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated in vivo that CCC-dependent recycling controls LDLR surface levels and plasma lipid handling, linking the complex to systemic physiology.\",\n      \"evidence\": \"Liver-specific knockout mice, CRISPR somatic editing, LDL uptake and LDLR localization assays\",\n      \"pmids\": [\"26965651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CCDC93-specific knockout not used here\", \"Mechanism of LDLR retrieval step unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the CCC complex as the lysosomal-degradation-protecting partner of SNX17 and Retriever, establishing the scope of cargo it recycles.\",\n      \"evidence\": \"Quantitative cell-surface proteomics, Co-IP, and loss-of-function recycling assays across >120 cargoes\",\n      \"pmids\": [\"28892079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CCDC93 physically couples to SNX17/Retriever not yet structurally resolved\", \"Selectivity rules for cargo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CCC complex integrity is interdependent, with COMMD proteins required to stabilize CCDC93 and CCDC22, clarifying assembly hierarchy.\",\n      \"evidence\": \"Liver-specific Commd knockout mice, targeted proteomics, CRISPR Ccdc22 deletion, western blotting\",\n      \"pmids\": [\"29545368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of complex assembly not defined\", \"Whether CCDC93 has roles outside the assembled complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the lipid-level mechanism by which the complex acts, linking CCDC93/CCC to MTMR2-controlled endosomal PI(3)P and WASH-dependent actin.\",\n      \"evidence\": \"siRNA depletion with PI(3)P biosensors, F-actin quantification, and MTMR2 phosphorylation/recruitment assays\",\n      \"pmids\": [\"31537807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic relationship between CCDC93 and MTMR2 not established\", \"Kinase responsible for MTMR2 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected human genetic variation in CCDC93 to LDL handling, showing CCDC93 dosage and stability directly tune LDLR surface levels.\",\n      \"evidence\": \"Population genetics with mouse overexpression and cellular ablation, LDLR surface and LDL uptake assays\",\n      \"pmids\": [\"31630160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional validation\", \"Mechanism by which p.Pro228Leu stabilizes protein not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed across multiple COMMD genes that the assembled complex including CCDC93 drives hepatic ATP7B recycling and copper excretion.\",\n      \"evidence\": \"Tissue-specific COMMD knockout mice, biochemical CCC integrity analysis, copper measurements\",\n      \"pmids\": [\"33262129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CCDC93-specific deletion not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the structural basis of CCDC93's scaffolding role, showing it bridges the COMMD core to Retriever and that cancer mutations break this coupling.\",\n      \"evidence\": \"Cryo-EM of Retriever, AlphaFold modeling, biochemical pulldowns, proteomics, disease-variant mutagenesis\",\n      \"pmids\": [\"38062209\", \"37397996\", \"37333304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics during cargo handoff not captured\", \"Membrane-bound state not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Determined the endogenous Commander architecture, placing CCDC22-CCDC93 as the scaffold linking the COMMD core to DENND10 and Retriever effector module.\",\n      \"evidence\": \"Cryo-EM of endogenous human Commander with MS-based composition validation\",\n      \"pmids\": [\"38459129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of DENND10 module within recycling not defined\", \"Dynamics of submodule engagement unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a vascular and mitochondrial requirement for CCDC93 in vivo, indicating phenotypes beyond cargo recycling and that the gene is developmentally essential.\",\n      \"evidence\": \"CRISPR Ccdc93 knockout mice (homozygous lethal), wire myography, RNA-Seq, plasma fatty acid and mitochondrial protein analysis\",\n      \"pmids\": [\"39250516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between recycling defects and mitochondrial dysfunction unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established CCDC93 as a Ritscher-Schinzel syndrome gene, mechanistically tying disease to disrupted Commander assembly and loss of SNX17-motif cargo at the surface.\",\n      \"evidence\": \"Patient mutation interactome analysis, cell-surface proteomics, CCDC93-deficient mouse models, cargo motif analysis\",\n      \"pmids\": [\"40601774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific basis of individual RSS features not dissected\", \"Relationship to vascular/mitochondrial phenotypes not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified WIPI2 as a CCDC93 partner defining a pathway-selective recycling route, refining how distinct cargo classes are sorted.\",\n      \"evidence\": \"Co-IP, FSSS-motif mutagenesis, and selective cargo trafficking assays (β1-integrin vs EGFR/GLUT1) (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.08.681146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Structural basis of WIPI2-CCDC93 interface not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CCC function to innate immunity, showing the complex is required for phagosome maturation and bacterial clearance via PI(3)P control.\",\n      \"evidence\": \"BMDM loss-of-function, phagosomal PI(3)P imaging, phagosome-lysosome fusion and bacterial clearance assays (preprint)\",\n      \"pmids\": [\"41473320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Whether CCDC93 acts identically on phagosomes and endosomes unverified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the broader CCDC93-dependent phenotypes (vascular tone, mitochondrial homeostasis, lysosomal secretion) mechanistically derive from endosomal recycling defects remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model connecting recycling defects to mitochondrial/vascular phenotypes\", \"Cargo-by-cargo selectivity rules of the complex not fully defined\", \"Membrane-engaged structural state of CCDC93 not captured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"complexes\": [\"CCC complex\", \"Commander complex\", \"Retriever-CCC complex\"],\n    \"partners\": [\"CCDC22\", \"FAM21\", \"SNX17\", \"MTMR2\", \"WIPI2\", \"COMMD1\", \"VPS35L\", \"DENND10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}