{"gene":"COMMD8","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2013,"finding":"COMMD8, like all COMMD proteins, binds to CCDC22, and COMMD8 acts in conjunction with CCDC22 to direct the degradation of IκB proteins, thereby promoting NF-κB activation. An XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins, resulting in decreased IκB ubiquitination and degradation.","method":"Co-immunoprecipitation, patient-derived cell functional assays (IκB ubiquitination and degradation), genetic association with XLID mutation","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding shown, functional consequence in patient-derived cells with two orthogonal methods (Co-IP and ubiquitination assay), single lab","pmids":["23563313"],"is_preprint":false},{"year":2019,"finding":"COMMD8 forms a stable complex with COMMD3 (COMMD3/8 complex) that acts as a signaling adaptor for chemoattractant receptors. COMMD8 stability depends on COMMD3. The COMMD3/8 complex is recruited to multiple chemoattractant receptors (e.g., CXCR4), selectively recruits GRK6, and promotes GRK6-mediated phosphorylation of the receptor and activation of β-arrestin-mediated signaling, thereby promoting lymphocyte chemotaxis. Deficiency of COMMD8 impaired B cell migration and humoral immune responses.","method":"Co-immunoprecipitation, genetic knockout (COMMD8-deficient mice), B cell migration assays, GRK6 recruitment and receptor phosphorylation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined cellular phenotype, GRK6 recruitment and phosphorylation assays, multiple orthogonal methods in a single rigorous study","pmids":["31088898"],"is_preprint":false},{"year":2023,"finding":"Celastrol covalently binds to and dissociates the COMMD3/8 complex, thereby inhibiting B cell migration, reducing antibody responses, and blocking arthritis progression. Mice expressing a celastrol-resistant mutant of the COMMD3/8 complex were insensitive to these effects, confirming that the COMMD3/8 complex is the direct pharmacological target of celastrol's immunosuppressive activity.","method":"Covalent binding assay (mass spectrometry/biochemistry), celastrol-resistant mutant mouse model, B cell migration assays, mouse model of rheumatoid arthritis","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — covalent binding demonstrated biochemically, celastrol-resistant mutant rescue experiment, in vivo arthritis model, multiple orthogonal methods","pmids":["37000855"],"is_preprint":false}],"current_model":"COMMD8 forms a stable heterodimeric complex with COMMD3 (whose presence is required for COMMD8 stability) that serves as a specificity adaptor at chemoattractant GPCRs, selectively recruiting GRK6 to promote receptor phosphorylation and β-arrestin signaling; it also cooperates with CCDC22 to facilitate IκB ubiquitination and degradation, thereby enabling NF-κB activation, and the COMMD3/8 complex is the direct covalent target of the anti-inflammatory natural compound celastrol."},"narrative":{"mechanistic_narrative":"COMMD8 is a COMM-domain protein that functions as a signaling adaptor controlling chemoattractant receptor responses and NF-κB activation in immune cells [PMID:31088898, PMID:23563313]. It forms a stable heterodimeric complex with COMMD3, on which its own stability depends, and this COMMD3/8 complex is recruited to chemoattractant GPCRs such as CXCR4 where it selectively recruits GRK6 to drive receptor phosphorylation and β-arrestin-mediated signaling, thereby promoting lymphocyte chemotaxis, B cell migration, and humoral immune responses [PMID:31088898]. In a separate role, COMMD8 cooperates with CCDC22 to direct the ubiquitination and degradation of IκB proteins, enabling NF-κB activation [PMID:23563313]. The COMMD3/8 complex is the direct covalent pharmacological target of the anti-inflammatory natural product celastrol, which dissociates the complex to suppress B cell migration and arthritis [PMID:37000855].","teleology":[{"year":2013,"claim":"Established that COMMD8 is not merely a passive COMMD family member but functionally couples to CCDC22 to regulate IκB turnover, placing it in the NF-κB activation pathway.","evidence":"Co-immunoprecipitation and IκB ubiquitination/degradation assays in patient-derived cells carrying an XLID-associated CCDC22 mutation","pmids":["23563313"],"confidence":"Medium","gaps":["Direct enzymatic role of COMMD8 in the ubiquitination machinery not defined","Single-lab finding; structural basis of COMMD8-CCDC22 interaction unresolved","Whether the NF-κB role is independent of the COMMD3/8 chemoattractant function not addressed"]},{"year":2019,"claim":"Defined COMMD8's principal mechanism as a COMMD3-dependent adaptor that confers GRK6 specificity at chemoattractant GPCRs, linking it causally to lymphocyte migration and humoral immunity.","evidence":"Reciprocal Co-IP, COMMD8-deficient mice, B cell migration assays, and GRK6 recruitment/receptor phosphorylation assays","pmids":["31088898"],"confidence":"High","gaps":["Structural basis for selective GRK6 (versus other GRK) recruitment unknown","Mechanism connecting receptor engagement to complex recruitment not detailed","Relationship to the earlier CCDC22/NF-κB role not reconciled"]},{"year":2023,"claim":"Identified the COMMD3/8 complex as the direct covalent target of celastrol, providing pharmacological validation that complex integrity is required for its immune function.","evidence":"Covalent binding biochemistry, celastrol-resistant mutant rescue mouse model, B cell migration and rheumatoid arthritis models","pmids":["37000855"],"confidence":"High","gaps":["Precise covalent residue and structural consequences of dissociation not fully mapped","Whether celastrol also perturbs the CCDC22/NF-κB function not addressed"]},{"year":null,"claim":"How COMMD8's two reported roles — GPCR/GRK6 adaptor and CCDC22-coupled IκB degradation — are mechanistically and structurally integrated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of COMMD8 in either complex","Substrate-recognition logic for selective GRK6 recruitment unknown","Catalytic versus scaffolding contribution to IκB ubiquitination undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":["COMMD3/8 complex"],"partners":["COMMD3","CCDC22","GRK6","CXCR4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NX08","full_name":"COMM domain-containing protein 8","aliases":[],"length_aa":183,"mass_kda":21.1,"function":"Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex (PubMed:37172566, PubMed:38459129). May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). May down-regulate activation of NF-kappa-B (PubMed:15799966)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NX08/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COMMD8","classification":"Not Classified","n_dependent_lines":174,"n_total_lines":1208,"dependency_fraction":0.14403973509933773},"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":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COMMD8","total_profiled":1310},"omim":[{"mim_id":"616656","title":"COMM DOMAIN-CONTAINING PROTEIN 8; COMMD8","url":"https://www.omim.org/entry/616656"},{"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":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COMMD8"},"hgnc":{"alias_symbol":["FLJ20502"],"prev_symbol":[]},"alphafold":{"accession":"Q9NX08","domains":[{"cath_id":"2.30.31","chopping":"114-181","consensus_level":"high","plddt":85.2344,"start":114,"end":181},{"cath_id":"1.10.246","chopping":"9-110","consensus_level":"high","plddt":91.9951,"start":9,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NX08","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NX08-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NX08-F1-predicted_aligned_error_v6.png","plddt_mean":87.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COMMD8","jax_strain_url":"https://www.jax.org/strain/search?query=COMMD8"},"sequence":{"accession":"Q9NX08","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NX08.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NX08/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NX08"}},"corpus_meta":[{"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":91,"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":"30982576","id":"PMC_30982576","title":"Long non-coding RNA MNX1-AS1 promotes hepatocellular carcinoma proliferation and invasion through targeting miR-218-5p/COMMD8 axis.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30982576","citation_count":44,"is_preprint":false},{"pmid":"37000855","id":"PMC_37000855","title":"Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex.","date":"2023","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37000855","citation_count":44,"is_preprint":false},{"pmid":"31088898","id":"PMC_31088898","title":"The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31088898","citation_count":36,"is_preprint":false},{"pmid":"33149680","id":"PMC_33149680","title":"LncRNA MALAT1 Aggravates the Progression of Non-Small Cell Lung Cancer by Stimulating the Expression of COMMD8 via Targeting miR-613.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33149680","citation_count":34,"is_preprint":false},{"pmid":"31566716","id":"PMC_31566716","title":"Long noncoding RNA LINC00657 induced by SP1 contributes to the non-small cell lung cancer progression through targeting miR-26b-5p/COMMD8 axis.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31566716","citation_count":26,"is_preprint":false},{"pmid":"34829930","id":"PMC_34829930","title":"Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34829930","citation_count":6,"is_preprint":false},{"pmid":"38596085","id":"PMC_38596085","title":"Integrated analysis of m6A regulator-mediated RNA methylation modification patterns and immune characteristics in Sjögren's syndrome.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38596085","citation_count":3,"is_preprint":false},{"pmid":"32559011","id":"PMC_32559011","title":"COMMD8 changes expression during initial phase of wasp venom immunotherapy.","date":"2020","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32559011","citation_count":2,"is_preprint":false},{"pmid":"34658711","id":"PMC_34658711","title":"IFNG, FCER1A, PCDHB10 expression as a new potential marker of efficacy in grass pollen allergen-specific immunotherapy.","date":"2021","source":"Postepy dermatologii i alergologii","url":"https://pubmed.ncbi.nlm.nih.gov/34658711","citation_count":2,"is_preprint":false},{"pmid":"41233790","id":"PMC_41233790","title":"Non-Lethal heat shock induces COMMD gene activation and enhances pathogen defense in Procambarus clarkii.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41233790","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8600,"output_tokens":994,"usd":0.020355,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7544,"output_tokens":1648,"usd":0.03946,"stage2_stop_reason":"end_turn"},"total_usd":0.059815,"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\": 2013,\n      \"finding\": \"COMMD8, like all COMMD proteins, binds to CCDC22, and COMMD8 acts in conjunction with CCDC22 to direct the degradation of IκB proteins, thereby promoting NF-κB activation. An XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins, resulting in decreased IκB ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, patient-derived cell functional assays (IκB ubiquitination and degradation), genetic association with XLID mutation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding shown, functional consequence in patient-derived cells with two orthogonal methods (Co-IP and ubiquitination assay), single lab\",\n      \"pmids\": [\"23563313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"COMMD8 forms a stable complex with COMMD3 (COMMD3/8 complex) that acts as a signaling adaptor for chemoattractant receptors. COMMD8 stability depends on COMMD3. The COMMD3/8 complex is recruited to multiple chemoattractant receptors (e.g., CXCR4), selectively recruits GRK6, and promotes GRK6-mediated phosphorylation of the receptor and activation of β-arrestin-mediated signaling, thereby promoting lymphocyte chemotaxis. Deficiency of COMMD8 impaired B cell migration and humoral immune responses.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockout (COMMD8-deficient mice), B cell migration assays, GRK6 recruitment and receptor phosphorylation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined cellular phenotype, GRK6 recruitment and phosphorylation assays, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31088898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celastrol covalently binds to and dissociates the COMMD3/8 complex, thereby inhibiting B cell migration, reducing antibody responses, and blocking arthritis progression. Mice expressing a celastrol-resistant mutant of the COMMD3/8 complex were insensitive to these effects, confirming that the COMMD3/8 complex is the direct pharmacological target of celastrol's immunosuppressive activity.\",\n      \"method\": \"Covalent binding assay (mass spectrometry/biochemistry), celastrol-resistant mutant mouse model, B cell migration assays, mouse model of rheumatoid arthritis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — covalent binding demonstrated biochemically, celastrol-resistant mutant rescue experiment, in vivo arthritis model, multiple orthogonal methods\",\n      \"pmids\": [\"37000855\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COMMD8 forms a stable heterodimeric complex with COMMD3 (whose presence is required for COMMD8 stability) that serves as a specificity adaptor at chemoattractant GPCRs, selectively recruiting GRK6 to promote receptor phosphorylation and β-arrestin signaling; it also cooperates with CCDC22 to facilitate IκB ubiquitination and degradation, thereby enabling NF-κB activation, and the COMMD3/8 complex is the direct covalent target of the anti-inflammatory natural compound celastrol.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COMMD8 is a COMM-domain protein that functions as a signaling adaptor controlling chemoattractant receptor responses and NF-κB activation in immune cells [#1, #0]. It forms a stable heterodimeric complex with COMMD3, on which its own stability depends, and this COMMD3/8 complex is recruited to chemoattractant GPCRs such as CXCR4 where it selectively recruits GRK6 to drive receptor phosphorylation and β-arrestin-mediated signaling, thereby promoting lymphocyte chemotaxis, B cell migration, and humoral immune responses [#1]. In a separate role, COMMD8 cooperates with CCDC22 to direct the ubiquitination and degradation of IκB proteins, enabling NF-κB activation [#0]. The COMMD3/8 complex is the direct covalent pharmacological target of the anti-inflammatory natural product celastrol, which dissociates the complex to suppress B cell migration and arthritis [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that COMMD8 is not merely a passive COMMD family member but functionally couples to CCDC22 to regulate IκB turnover, placing it in the NF-κB activation pathway.\",\n      \"evidence\": \"Co-immunoprecipitation and IκB ubiquitination/degradation assays in patient-derived cells carrying an XLID-associated CCDC22 mutation\",\n      \"pmids\": [\"23563313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct enzymatic role of COMMD8 in the ubiquitination machinery not defined\",\n        \"Single-lab finding; structural basis of COMMD8-CCDC22 interaction unresolved\",\n        \"Whether the NF-κB role is independent of the COMMD3/8 chemoattractant function not addressed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined COMMD8's principal mechanism as a COMMD3-dependent adaptor that confers GRK6 specificity at chemoattractant GPCRs, linking it causally to lymphocyte migration and humoral immunity.\",\n      \"evidence\": \"Reciprocal Co-IP, COMMD8-deficient mice, B cell migration assays, and GRK6 recruitment/receptor phosphorylation assays\",\n      \"pmids\": [\"31088898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for selective GRK6 (versus other GRK) recruitment unknown\",\n        \"Mechanism connecting receptor engagement to complex recruitment not detailed\",\n        \"Relationship to the earlier CCDC22/NF-κB role not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the COMMD3/8 complex as the direct covalent target of celastrol, providing pharmacological validation that complex integrity is required for its immune function.\",\n      \"evidence\": \"Covalent binding biochemistry, celastrol-resistant mutant rescue mouse model, B cell migration and rheumatoid arthritis models\",\n      \"pmids\": [\"37000855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise covalent residue and structural consequences of dissociation not fully mapped\",\n        \"Whether celastrol also perturbs the CCDC22/NF-κB function not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COMMD8's two reported roles — GPCR/GRK6 adaptor and CCDC22-coupled IκB degradation — are mechanistically and structurally integrated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of COMMD8 in either complex\",\n        \"Substrate-recognition logic for selective GRK6 recruitment unknown\",\n        \"Catalytic versus scaffolding contribution to IκB ubiquitination undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"COMMD3/8 complex\"],\n    \"partners\": [\"COMMD3\", \"CCDC22\", \"GRK6\", \"CXCR4\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}