{"gene":"CCDC22","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2013,"finding":"All COMMD proteins bind to CCDC22, and an XLID-associated CCDC22 mutation decreases CCDC22 protein expression and impairs its binding to COMMD proteins. CCDC22 participates in NF-κB activation by facilitating IκB ubiquitination and degradation, acting in conjunction with COMMD8.","method":"Co-immunoprecipitation, patient-derived cell lines, Western blot, NF-κB reporter assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, patient-derived cells, multiple orthogonal methods; replicated in subsequent studies","pmids":["23563313"],"is_preprint":false},{"year":2019,"finding":"The CCC complex (CCDC22/CCDC93/COMMD proteins) regulates endosomal phosphatidylinositol-3-phosphate (PI(3)P) levels by controlling phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. CCC depletion leads to elevated endosomal PI(3)P, enhanced WASH recruitment and activation, excess F-actin at endosomes, and trapping of internalized receptors. CCC and retriever share a common subunit VPS35L.","method":"siRNA depletion, phosphoinositide quantification, Co-immunoprecipitation, fluorescence microscopy, endosomal fractionation, F-actin staining","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study with mechanistic follow-up; strong moderate evidence","pmids":["31537807"],"is_preprint":false},{"year":2014,"finding":"A missense variant (p.Tyr557Cys) in CCDC22 leads to decreased CCDC22 protein expression and increased WASH1 expression in patient lymphoblastoid cell lines, placing CCDC22 upstream of WASH1 in endosomal recycling.","method":"Western blot of patient-derived immortalized lymphoblastoid cell lines, whole-exome sequencing","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 3 — single method (Western blot) in patient cells; single lab","pmids":["24916641"],"is_preprint":false},{"year":2025,"finding":"CCDC22 missense mutations p.E208K and p.P172R impair CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding, demonstrating that CCDC22 directly binds COMMD4 for complex integrity.","method":"Co-immunoprecipitation, mutant protein expression, complex assembly assays","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with mutagenesis; single lab","pmids":["40448120"],"is_preprint":false}],"current_model":"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that functions in endosomal protein recycling by binding COMMD proteins (particularly COMMD4/COMMD8) and regulating endosomal PI(3)P levels through control of MTMR2 phosphatase recruitment, thereby limiting WASH-dependent actin nucleation; CCDC22 also participates in NF-κB activation by facilitating IκB ubiquitination and degradation in conjunction with COMMD8."},"narrative":{"teleology":[{"year":2013,"claim":"Establishing CCDC22 as a COMMD-binding protein and NF-κB regulator resolved how COMMD proteins are physically assembled and linked to IκB degradation.","evidence":"Reciprocal co-immunoprecipitation, patient-derived cell lines with XLID-associated CCDC22 mutation, NF-κB reporter assays","pmids":["23563313"],"confidence":"High","gaps":["Structural basis of CCDC22–COMMD interaction not resolved","Mechanism by which CCDC22/COMMD8 facilitates IκB ubiquitination (E3 ligase identity) not identified","Whether CCDC22 has additional functions beyond NF-κB signaling was unknown"]},{"year":2014,"claim":"Identification of an additional CCDC22 missense variant (p.Tyr557Cys) in XLID patients linked reduced CCDC22 protein to increased WASH1 expression, revealing an endosomal trafficking axis upstream of the WASH complex.","evidence":"Western blot of patient-derived lymphoblastoid cell lines, whole-exome sequencing","pmids":["24916641"],"confidence":"Medium","gaps":["Single-method (Western blot) observation in one patient cell line; awaits independent replication","Mechanism connecting CCDC22 loss to WASH1 upregulation was not determined"]},{"year":2019,"claim":"Demonstrating that the CCC complex controls endosomal PI(3)P through MTMR2 phosphatase recruitment explained how CCDC22 loss leads to excessive WASH-driven actin nucleation and receptor trapping, unifying the NF-κB and endosomal recycling functions under a single complex.","evidence":"siRNA depletion, phosphoinositide quantification, co-immunoprecipitation, fluorescence microscopy, endosomal fractionation, F-actin staining","pmids":["31537807"],"confidence":"High","gaps":["Whether CCDC22 directly contacts MTMR2 or acts through other CCC subunits is unclear","Identity of cargo receptors whose recycling depends specifically on CCDC22 was not catalogued","Relationship between PI(3)P regulation and NF-κB signaling roles of CCC not established"]},{"year":2025,"claim":"Mapping disease-associated CCDC22 mutations to a conserved COMMD4-binding surface established the structural requirement for CCDC22–COMMD4 interaction in CCC complex assembly.","evidence":"Co-immunoprecipitation with mutant CCDC22 constructs (E208K, P172R), complex assembly assays","pmids":["40448120"],"confidence":"Medium","gaps":["Atomic-resolution structure of CCDC22–COMMD4 interface not yet determined","Whether these mutations differentially affect endosomal versus NF-κB functions remains untested"]},{"year":null,"claim":"Open questions include the high-resolution structure of the intact CCC complex, whether CCDC22 has catalytic or scaffolding activity independent of COMMD proteins, and how the PI(3)P regulatory and NF-κB signaling functions of CCC are coordinated in vivo.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic structure of full CCC complex","No in vivo animal model specifically testing CCDC22 endosomal function","Relationship between CCC-retriever supercomplex and CCDC22-specific contributions not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]}],"complexes":["CCC (COMMD/CCDC22/CCDC93)"],"partners":["CCDC93","COMMD4","COMMD8","MTMR2","WASH1","VPS35L"],"other_free_text":[]},"mechanistic_narrative":"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that functions in endosomal protein recycling and NF-κB signaling. CCDC22 directly binds all ten COMMD proteins—with COMMD4 binding being critical for complex integrity—and acts together with COMMD8 to facilitate IκB ubiquitination and degradation, thereby promoting NF-κB activation [PMID:23563313, PMID:40448120]. In the endosomal compartment, the CCC complex controls phosphatidylinositol-3-phosphate (PI(3)P) levels by regulating phosphorylation and recruitment of the PI(3)P phosphatase MTMR2; loss of CCC function elevates endosomal PI(3)P, leading to excessive WASH-dependent actin nucleation and trapping of internalized receptors [PMID:31537807]. X-linked intellectual disability (XLID)-associated missense mutations in CCDC22 reduce protein expression and disrupt COMMD binding, establishing CCDC22 as a causative gene for this disorder [PMID:23563313, PMID:24916641]."},"prefetch_data":{"uniprot":{"accession":"O60826","full_name":"Coiled-coil domain-containing protein 22","aliases":[],"length_aa":627,"mass_kda":70.8,"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). Involved in regulation of NF-kappa-B signaling (PubMed:23563313). Promotes ubiquitination of I-kappa-B-kinase subunit IKBKB and its subsequent proteasomal degradation leading to NF-kappa-B activation; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex (PubMed:23563313). May down-regulate NF-kappa-B activity via association with COMMD1 and involving a CUL2-dependent E3 ubiquitin ligase complex. Regulates the cellular localization of COMM domain-containing proteins, such as COMMD1 and COMMD10 (PubMed:23563313). Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels. 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). Plays a role in copper ion homeostasis (PubMed:25355947). 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 (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":"Endosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/O60826/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC22","classification":"Not Classified","n_dependent_lines":175,"n_total_lines":1208,"dependency_fraction":0.14486754966887416},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101997","cell_line_id":"CID000262","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"C16ORF62","stoichiometry":10.0},{"gene":"CCDC93","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":"VPS29","stoichiometry":10.0},{"gene":"COMMD8","stoichiometry":10.0},{"gene":"COMMD3-BMI1;COMMD3;BMI1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000262","total_profiled":1310},"omim":[{"mim_id":"620553","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 93; CCDC93","url":"https://www.omim.org/entry/620553"},{"mim_id":"619135","title":"RITSCHER-SCHINZEL SYNDROME 3; RTSC3","url":"https://www.omim.org/entry/619135"},{"mim_id":"618981","title":"VPS35 ENDOSOMAL PROTEIN-SORTING FACTOR-LIKE; VPS35L","url":"https://www.omim.org/entry/618981"},{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"616656","title":"COMM DOMAIN-CONTAINING PROTEIN 8; COMMD8","url":"https://www.omim.org/entry/616656"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC22"},"hgnc":{"alias_symbol":["JM1"],"prev_symbol":["CXorf37"]},"alphafold":{"accession":"O60826","domains":[{"cath_id":"-","chopping":"121-162","consensus_level":"medium","plddt":74.4002,"start":121,"end":162},{"cath_id":"1.10.418","chopping":"2-111","consensus_level":"high","plddt":81.1306,"start":2,"end":111},{"cath_id":"1.20.1480","chopping":"507-597","consensus_level":"medium","plddt":92.7571,"start":507,"end":597}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60826","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60826-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60826-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC22","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC22"},"sequence":{"accession":"O60826","fasta_url":"https://rest.uniprot.org/uniprotkb/O60826.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60826/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60826"}},"corpus_meta":[{"pmid":"31537807","id":"PMC_31537807","title":"Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31537807","citation_count":94,"is_preprint":false},{"pmid":"23563313","id":"PMC_23563313","title":"CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23563313","citation_count":90,"is_preprint":false},{"pmid":"18248983","id":"PMC_18248983","title":"Biological hydrogen production by immobilized cells of Clostridium tyrobutyricum JM1 isolated from a food waste treatment process.","date":"2008","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/18248983","citation_count":47,"is_preprint":false},{"pmid":"24916641","id":"PMC_24916641","title":"Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24916641","citation_count":45,"is_preprint":false},{"pmid":"11770015","id":"PMC_11770015","title":"Sanguinarine induces bimodal cell death in K562 but not in high Bcl-2-expressing JM1 cells.","date":"2001","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/11770015","citation_count":26,"is_preprint":false},{"pmid":"32600763","id":"PMC_32600763","title":"Lactobacillus gasseri JM1 with potential probiotic characteristics alleviates inflammatory response by activating the PI3K/Akt signaling pathway in vitro.","date":"2020","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/32600763","citation_count":25,"is_preprint":false},{"pmid":"36615796","id":"PMC_36615796","title":"Lactobacillus gasseri JM1 Isolated from Infant Feces Alleviates Colitis in Mice via Protecting the Intestinal Barrier.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36615796","citation_count":23,"is_preprint":false},{"pmid":"37923200","id":"PMC_37923200","title":"The probiotic fermented milk of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 alleviates constipation via improving gastrointestinal motility and gut microbiota.","date":"2023","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/37923200","citation_count":20,"is_preprint":false},{"pmid":"36839197","id":"PMC_36839197","title":"The Probiotic Combination of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 Alleviates Gastrointestinal Motility Disorder via Improving Gut Microbiota.","date":"2023","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36839197","citation_count":17,"is_preprint":false},{"pmid":"34020006","id":"PMC_34020006","title":"Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34020006","citation_count":16,"is_preprint":false},{"pmid":"23468088","id":"PMC_23468088","title":"Indirubin-3'-monoxime promotes autophagic and apoptotic death in JM1 human acute lymphoblastic leukemia cells and K562 human chronic myelogenous leukemia cells.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23468088","citation_count":15,"is_preprint":false},{"pmid":"39426154","id":"PMC_39426154","title":"CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia.","date":"2024","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/39426154","citation_count":12,"is_preprint":false},{"pmid":"27888057","id":"PMC_27888057","title":"Association between rs2294020 in X-linked CCDC22 and susceptibility to autoimmune diseases with focus on systemic lupus 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melanoma.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33278894","citation_count":6,"is_preprint":false},{"pmid":"35646503","id":"PMC_35646503","title":"2,4-Diacetylphloroglucinol producing Pseudomonas fluorescens JM-1 for management of ear rot disease caused by Fusarium moniliforme in Zea mays L.","date":"2022","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/35646503","citation_count":2,"is_preprint":false},{"pmid":"28470452","id":"PMC_28470452","title":"CCDC22 gene polymorphism is associated with advanced stages of endometriosis in a sample of Brazilian women.","date":"2017","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28470452","citation_count":2,"is_preprint":false},{"pmid":"36618652","id":"PMC_36618652","title":"CCDC22 and CCDC93, two potential retriever-interacting proteins, are required for root and root hair growth in Arabidopsis.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/36618652","citation_count":1,"is_preprint":false},{"pmid":"40448120","id":"PMC_40448120","title":"CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome.","date":"2025","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40448120","citation_count":1,"is_preprint":false},{"pmid":"28935728","id":"PMC_28935728","title":"Draft Genome Sequence of Pantoea agglomerans JM1, a Strain Isolated from Soil Polluted by Industrial Production of Beta-Lactam Antibiotics That Exhibits Valacyclovir-Like Hydrolase Activity.","date":"2017","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/28935728","citation_count":1,"is_preprint":false},{"pmid":"33059814","id":"PMC_33059814","title":"[Ritscher-Schinzel syndrome caused by CCDC22 gene mutation: a case report].","date":"2020","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/33059814","citation_count":0,"is_preprint":false},{"pmid":"41643309","id":"PMC_41643309","title":"Integrated proteomics and metabolomics revealed the influence of ultrasonic cavitation effects on the physicochemical properties and metabolic components during Lactobacillus gasseri JM1 fermentation in soymilk.","date":"2026","source":"Ultrasonics sonochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41643309","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12592,"output_tokens":1021,"usd":0.026545},"stage2":{"model":"claude-opus-4-6","input_tokens":4235,"output_tokens":1571,"usd":0.090675},"total_usd":0.11722,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"All COMMD proteins bind to CCDC22, and an XLID-associated CCDC22 mutation decreases CCDC22 protein expression and impairs its binding to COMMD proteins. CCDC22 participates in NF-κB activation by facilitating IκB ubiquitination and degradation, acting in conjunction with COMMD8.\",\n      \"method\": \"Co-immunoprecipitation, patient-derived cell lines, Western blot, NF-κB reporter assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, patient-derived cells, multiple orthogonal methods; replicated in subsequent studies\",\n      \"pmids\": [\"23563313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CCC complex (CCDC22/CCDC93/COMMD proteins) regulates endosomal phosphatidylinositol-3-phosphate (PI(3)P) levels by controlling phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. CCC depletion leads to elevated endosomal PI(3)P, enhanced WASH recruitment and activation, excess F-actin at endosomes, and trapping of internalized receptors. CCC and retriever share a common subunit VPS35L.\",\n      \"method\": \"siRNA depletion, phosphoinositide quantification, Co-immunoprecipitation, fluorescence microscopy, endosomal fractionation, F-actin staining\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study with mechanistic follow-up; strong moderate evidence\",\n      \"pmids\": [\"31537807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A missense variant (p.Tyr557Cys) in CCDC22 leads to decreased CCDC22 protein expression and increased WASH1 expression in patient lymphoblastoid cell lines, placing CCDC22 upstream of WASH1 in endosomal recycling.\",\n      \"method\": \"Western blot of patient-derived immortalized lymphoblastoid cell lines, whole-exome sequencing\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single method (Western blot) in patient cells; single lab\",\n      \"pmids\": [\"24916641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC22 missense mutations p.E208K and p.P172R impair CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding, demonstrating that CCDC22 directly binds COMMD4 for complex integrity.\",\n      \"method\": \"Co-immunoprecipitation, mutant protein expression, complex assembly assays\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutagenesis; single lab\",\n      \"pmids\": [\"40448120\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that functions in endosomal protein recycling by binding COMMD proteins (particularly COMMD4/COMMD8) and regulating endosomal PI(3)P levels through control of MTMR2 phosphatase recruitment, thereby limiting WASH-dependent actin nucleation; CCDC22 also participates in NF-κB activation by facilitating IκB ubiquitination and degradation in conjunction with COMMD8.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that functions in endosomal protein recycling and NF-κB signaling. CCDC22 directly binds all ten COMMD proteins—with COMMD4 binding being critical for complex integrity—and acts together with COMMD8 to facilitate IκB ubiquitination and degradation, thereby promoting NF-κB activation [PMID:23563313, PMID:40448120]. In the endosomal compartment, the CCC complex controls phosphatidylinositol-3-phosphate (PI(3)P) levels by regulating phosphorylation and recruitment of the PI(3)P phosphatase MTMR2; loss of CCC function elevates endosomal PI(3)P, leading to excessive WASH-dependent actin nucleation and trapping of internalized receptors [PMID:31537807]. X-linked intellectual disability (XLID)-associated missense mutations in CCDC22 reduce protein expression and disrupt COMMD binding, establishing CCDC22 as a causative gene for this disorder [PMID:23563313, PMID:24916641].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing CCDC22 as a COMMD-binding protein and NF-κB regulator resolved how COMMD proteins are physically assembled and linked to IκB degradation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, patient-derived cell lines with XLID-associated CCDC22 mutation, NF-κB reporter assays\",\n      \"pmids\": [\"23563313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of CCDC22–COMMD interaction not resolved\",\n        \"Mechanism by which CCDC22/COMMD8 facilitates IκB ubiquitination (E3 ligase identity) not identified\",\n        \"Whether CCDC22 has additional functions beyond NF-κB signaling was unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of an additional CCDC22 missense variant (p.Tyr557Cys) in XLID patients linked reduced CCDC22 protein to increased WASH1 expression, revealing an endosomal trafficking axis upstream of the WASH complex.\",\n      \"evidence\": \"Western blot of patient-derived lymphoblastoid cell lines, whole-exome sequencing\",\n      \"pmids\": [\"24916641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-method (Western blot) observation in one patient cell line; awaits independent replication\",\n        \"Mechanism connecting CCDC22 loss to WASH1 upregulation was not determined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that the CCC complex controls endosomal PI(3)P through MTMR2 phosphatase recruitment explained how CCDC22 loss leads to excessive WASH-driven actin nucleation and receptor trapping, unifying the NF-κB and endosomal recycling functions under a single complex.\",\n      \"evidence\": \"siRNA depletion, phosphoinositide quantification, co-immunoprecipitation, fluorescence microscopy, endosomal fractionation, F-actin staining\",\n      \"pmids\": [\"31537807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CCDC22 directly contacts MTMR2 or acts through other CCC subunits is unclear\",\n        \"Identity of cargo receptors whose recycling depends specifically on CCDC22 was not catalogued\",\n        \"Relationship between PI(3)P regulation and NF-κB signaling roles of CCC not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapping disease-associated CCDC22 mutations to a conserved COMMD4-binding surface established the structural requirement for CCDC22–COMMD4 interaction in CCC complex assembly.\",\n      \"evidence\": \"Co-immunoprecipitation with mutant CCDC22 constructs (E208K, P172R), complex assembly assays\",\n      \"pmids\": [\"40448120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Atomic-resolution structure of CCDC22–COMMD4 interface not yet determined\",\n        \"Whether these mutations differentially affect endosomal versus NF-κB functions remains untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Open questions include the high-resolution structure of the intact CCC complex, whether CCDC22 has catalytic or scaffolding activity independent of COMMD proteins, and how the PI(3)P regulatory and NF-κB signaling functions of CCC are coordinated in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No atomic structure of full CCC complex\",\n        \"No in vivo animal model specifically testing CCDC22 endosomal function\",\n        \"Relationship between CCC-retriever supercomplex and CCDC22-specific contributions not dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"CCC (COMMD/CCDC22/CCDC93)\"\n    ],\n    \"partners\": [\n      \"CCDC93\",\n      \"COMMD4\",\n      \"COMMD8\",\n      \"MTMR2\",\n      \"WASH1\",\n      \"VPS35L\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}