{"gene":"CCDC92","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2020,"finding":"CCDC92 is a substrate of Tau Tubulin Kinase 2 (TTBK2); TTBK2 phosphorylates CCDC92 in vitro and in vivo, identifying CCDC92 as part of the TTBK2-dependent ciliogenesis phosphorylation network.","method":"In vitro kinase assay, in vivo phosphorylation analysis, mass spectrometry phosphosite mapping","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay combined with in vivo phosphorylation and MS-based phosphosite mapping","pmids":["32129703"],"is_preprint":false},{"year":2020,"finding":"CCDC92 acts as an interferon-stimulated gene that inhibits Ebola virus transcription and virion formation through a direct interaction with the viral nucleoprotein NP.","method":"Overexpression screen of ~400 ISGs, mechanistic follow-up with viral transcription/replication assays and protein interaction studies with viral NP","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype (reduced viral titers) plus interaction with viral NP, but single lab study","pmids":["32528005"],"is_preprint":false},{"year":2022,"finding":"Whole-body Ccdc92 knockout in mice reduces obesity, increases insulin sensitivity under high-fat diet, inhibits macrophage infiltration and fibrosis in white adipose tissue, increases energy expenditure, attenuates hepatic steatosis, and suppresses NLRP3 inflammasome activation in WAT.","method":"Whole-body knockout mouse model with metabolic phenotyping (body weight, insulin tolerance, energy expenditure, histology, inflammasome assays)","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with multiple defined metabolic phenotypes, single lab","pmids":["36594018"],"is_preprint":false},{"year":2023,"finding":"Podocyte-specific deletion of Ccdc92 ameliorates podocyte injury and ectopic lipid deposition in diabetic kidney disease; CCDC92 promotes podocyte lipotoxicity at least in part through ABCA1 signaling-mediated lipid homeostasis.","method":"Podocyte-specific knockout mouse models (db/db and HFD/STZ), histology, lipid accumulation assays, ABCA1 pathway analysis","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO with defined cellular phenotype and pathway placement, single lab","pmids":["37952690"],"is_preprint":false},{"year":2024,"finding":"CCDC92 promotes podocyte lipid accumulation by inhibiting cholesterol efflux; mechanistically, CCDC92 promotes degradation of the cholesterol transporter ABCA1 by upregulating PA28α-mediated proteasome activity, thereby reducing cholesterol efflux and causing podocyte injury.","method":"Podocyte-specific Ccdc92 knockout mice, proteasome activity assays, ABCA1 protein stability assays, PA28α pathway interrogation","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO with mechanistic dissection of PA28α/ABCA1/cholesterol efflux axis, single lab","pmids":["38228909"],"is_preprint":false},{"year":2025,"finding":"CCDC92 is required for spermiogenesis; its deficiency causes severe sperm head and flagellum abnormalities with deformed manchette structures, impaired nucleus elongation, detached acrosomes, and male infertility. CCDC92 physically interacts with intraflagellar transport (IFT) complex components and colocalizes with IFT proteins at the manchette. CCDC92 is also required for proper flagellar distribution of axonemal microtubule inner proteins.","method":"Ccdc92 knockout mice, electron microscopy ultrastructural analysis, co-immunoprecipitation with IFT components, colocalization imaging, quantitative proteomics","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 — KO with defined cellular phenotype, reciprocal interaction studies, colocalization, and quantitative proteomics in one study","pmids":["41378450"],"is_preprint":false},{"year":2025,"finding":"CCDC92 localizes to the ciliary tip and to centriole distal appendages; in Kif13b-/- cells, CCDC92 is released into large extracellular vesicles and is depleted from the ciliary tip, indicating that KIF13B controls ciliary CCDC92 content.","method":"Live-cell and immunofluorescence imaging, Kif13b knockout cells, extracellular vesicle proteomic analysis, subcellular fractionation","journal":"Current biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by imaging tied to functional consequence (EV release), single lab","pmids":["40930094"],"is_preprint":false},{"year":2019,"finding":"The CCDC92 S70C missense variant is associated specifically with increased leg fat mass and reduced visceral fat; the minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue, linking CCDC92 coding variation to fat depot-specific regulation.","method":"DXA imaging GWAS in ~17k participants, adipose tissue gene expression analysis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 — genetic association with expression correlation, no direct functional mechanism demonstrated","pmids":["31145760"],"is_preprint":false}],"current_model":"CCDC92 is a coiled-coil domain-containing protein that localizes to centriole distal appendages and the ciliary tip where it interacts with intraflagellar transport (IFT) complex components; it is phosphorylated by TTBK2 kinase as part of the ciliogenesis initiation pathway, is required for manchette-dependent spermatid shaping and male fertility, and in metabolic tissues promotes lipid accumulation by driving PA28α-mediated proteasomal degradation of the cholesterol transporter ABCA1, thereby suppressing cholesterol efflux and contributing to podocyte lipotoxicity, adipose inflammation, and insulin resistance."},"narrative":{"teleology":[{"year":2019,"claim":"A coding variant in CCDC92 (S70C) was linked to fat depot-specific body composition differences, providing the first hint that CCDC92 influences adipose biology, though no direct mechanism was demonstrated.","evidence":"DXA-imaging GWAS in ~17k participants with adipose tissue expression analysis","pmids":["31145760"],"confidence":"Low","gaps":["No causal mechanism connecting the S70C variant to fat distribution was established","No functional assay testing variant effect on protein activity","Association has not been confirmed in independent cohorts with functional follow-up"]},{"year":2020,"claim":"Identification of CCDC92 as a TTBK2 substrate placed it within the kinase-dependent ciliogenesis initiation pathway, establishing its first molecular link to centrosome/cilium biology.","evidence":"In vitro kinase assay, in vivo phosphorylation, and mass spectrometry phosphosite mapping","pmids":["32129703"],"confidence":"High","gaps":["Functional consequence of TTBK2-mediated phosphorylation on CCDC92 localization or activity was not determined","Whether phosphorylation is required for ciliogenesis was not tested"]},{"year":2020,"claim":"CCDC92 was identified as an interferon-stimulated gene with antiviral activity against Ebola virus, revealing a role outside cilia through direct interaction with the viral nucleoprotein NP.","evidence":"Overexpression screen of ~400 ISGs with viral transcription/replication assays and NP interaction studies","pmids":["32528005"],"confidence":"Medium","gaps":["Endogenous CCDC92 requirement for antiviral defense was not tested (loss-of-function)","Mechanism by which CCDC92 inhibits NP-dependent transcription is unclear","Breadth of antiviral activity beyond Ebola virus is unknown"]},{"year":2022,"claim":"Whole-body Ccdc92 knockout in mice established that CCDC92 is a pro-obesity, pro-inflammatory factor whose loss protects against diet-induced metabolic syndrome, resolving a key question raised by human genetic associations.","evidence":"Whole-body KO mice with metabolic phenotyping including body weight, insulin tolerance, energy expenditure, histology, and inflammasome assays under HFD","pmids":["36594018"],"confidence":"Medium","gaps":["Cell-autonomous versus systemic contributions were not dissected","Molecular target(s) downstream of CCDC92 in adipose tissue were not identified in this study"]},{"year":2023,"claim":"Podocyte-specific Ccdc92 deletion demonstrated a cell-autonomous role in promoting lipotoxicity in diabetic kidney disease and implicated ABCA1 signaling as a downstream pathway, narrowing the metabolic mechanism to cholesterol homeostasis.","evidence":"Podocyte-specific KO in db/db and HFD/STZ diabetic mouse models with lipid accumulation and ABCA1 pathway analysis","pmids":["37952690"],"confidence":"Medium","gaps":["Direct biochemical interaction between CCDC92 and ABCA1 pathway components was not shown","Whether the ABCA1 axis operates in adipocytes or hepatocytes was not tested"]},{"year":2024,"claim":"The mechanism of ABCA1 downregulation was resolved: CCDC92 upregulates PA28α-mediated proteasome activity to promote ABCA1 degradation, thereby blocking cholesterol efflux — the first complete molecular pathway for CCDC92's metabolic function.","evidence":"Podocyte-specific KO mice, proteasome activity assays, ABCA1 protein stability assays, PA28α pathway interrogation","pmids":["38228909"],"confidence":"Medium","gaps":["How CCDC92 activates PA28α is unknown (direct binding vs. transcriptional upregulation vs. intermediate)","Whether the PA28α–ABCA1 degradation axis operates in non-podocyte metabolic tissues remains untested","Single lab; independent confirmation is lacking"]},{"year":2025,"claim":"CCDC92 was shown to be essential for spermiogenesis through its interaction with IFT complex components at the manchette, establishing its first in vivo requirement in an IFT-dependent process and explaining the male infertility phenotype.","evidence":"Ccdc92 KO mice, electron microscopy, co-immunoprecipitation with IFT components, colocalization imaging, quantitative proteomics","pmids":["41378450"],"confidence":"High","gaps":["Which specific IFT subunits are direct binding partners versus indirect interactors is not fully resolved","Whether CCDC92 phosphorylation by TTBK2 regulates its IFT interactions was not tested"]},{"year":2025,"claim":"Precise subcellular localization of CCDC92 to centriole distal appendages and the ciliary tip was established, and KIF13B was identified as a regulator of CCDC92 ciliary retention, connecting CCDC92 to kinesin-dependent ciliary trafficking.","evidence":"Live-cell and immunofluorescence imaging, Kif13b KO cells, extracellular vesicle proteomics, subcellular fractionation","pmids":["40930094"],"confidence":"Medium","gaps":["Whether loss of ciliary-tip CCDC92 affects cilia signaling or length is not determined","Mechanism by which KIF13B retains CCDC92 at the tip (direct cargo vs. indirect) is unresolved"]},{"year":null,"claim":"How CCDC92's ciliary/centriolar and metabolic functions are mechanistically related — or whether they represent independent activities of the protein — remains an open question.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study has tested whether ciliary localization is required for CCDC92's metabolic role","Structural basis of CCDC92 interactions (coiled-coil domain mapping to IFT vs. PA28α) is unknown","Whether TTBK2 phosphorylation controls any non-ciliary function of CCDC92 has not been explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5]}],"complexes":[],"partners":["TTBK2","KIF13B","ABCA1","PSME1"],"other_free_text":[]},"mechanistic_narrative":"CCDC92 is a coiled-coil domain-containing protein that functions at the intersection of ciliogenesis, intraflagellar transport, and lipid homeostasis. It localizes to centriole distal appendages and the ciliary tip, is phosphorylated by TTBK2 as part of the ciliogenesis initiation cascade, and physically interacts with IFT complex components to support manchette-dependent spermatid shaping and flagellar assembly, such that its loss causes male infertility with severe sperm head and flagellum abnormalities [PMID:32129703, PMID:41378450, PMID:40930094]. In metabolic tissues, CCDC92 promotes lipid accumulation by driving PA28α-mediated proteasomal degradation of the cholesterol transporter ABCA1, thereby suppressing cholesterol efflux; whole-body knockout reduces diet-induced obesity, insulin resistance, adipose inflammation, and hepatic steatosis, while podocyte-specific deletion ameliorates diabetic kidney injury and ectopic lipid deposition [PMID:36594018, PMID:37952690, PMID:38228909]. CCDC92 also functions as an interferon-stimulated gene that inhibits Ebola virus transcription and virion formation through direct interaction with the viral nucleoprotein NP [PMID:32528005]."},"prefetch_data":{"uniprot":{"accession":"Q53HC0","full_name":"Coiled-coil domain-containing protein 92","aliases":["Limkain beta-2"],"length_aa":331,"mass_kda":37.0,"function":"Interferon-stimulated protein that plays a role in innate immunity. Strongly inhibits ebolavirus transcription and replication. Forms a complex with viral RNA-bound nucleocapsid NP and thereby prevents the transport of NP to the cell surface","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q53HC0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC92","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCDC92","total_profiled":1310},"omim":[{"mim_id":"614848","title":"CENTROSOMAL PROTEIN, 164-KD; CEP164","url":"https://www.omim.org/entry/614848"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":138.0}],"url":"https://www.proteinatlas.org/search/CCDC92"},"hgnc":{"alias_symbol":["FLJ22471"],"prev_symbol":[]},"alphafold":{"accession":"Q53HC0","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53HC0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53HC0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53HC0-F1-predicted_aligned_error_v6.png","plddt_mean":73.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC92","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC92"},"sequence":{"accession":"Q53HC0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53HC0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53HC0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53HC0"}},"corpus_meta":[{"pmid":"28869590","id":"PMC_28869590","title":"Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28869590","citation_count":201,"is_preprint":false},{"pmid":"28714974","id":"PMC_28714974","title":"Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28714974","citation_count":184,"is_preprint":false},{"pmid":"32129703","id":"PMC_32129703","title":"Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2.","date":"2020","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32129703","citation_count":42,"is_preprint":false},{"pmid":"32528005","id":"PMC_32528005","title":"Identification of interferon-stimulated genes that attenuate Ebola virus infection.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32528005","citation_count":36,"is_preprint":false},{"pmid":"15768393","id":"PMC_15768393","title":"Analysis of microsatellite markers and single nucleotide polymorphisms in candidate genes for susceptibility to bipolar affective disorder in the chromosome 12Q24.31 region.","date":"2005","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15768393","citation_count":31,"is_preprint":false},{"pmid":"37952690","id":"PMC_37952690","title":"CCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease.","date":"2023","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/37952690","citation_count":27,"is_preprint":false},{"pmid":"35785618","id":"PMC_35785618","title":"Single-cell sequencing reveals CD133+CD44--originating evolution and novel stemness related variants in human colorectal cancer.","date":"2022","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/35785618","citation_count":20,"is_preprint":false},{"pmid":"37540242","id":"PMC_37540242","title":"Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes.","date":"2023","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/37540242","citation_count":16,"is_preprint":false},{"pmid":"38457382","id":"PMC_38457382","title":"Sedentary behavior, physical activity, sleep duration and obesity risk: Mendelian randomization study.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38457382","citation_count":15,"is_preprint":false},{"pmid":"36594018","id":"PMC_36594018","title":"Genetic ablation of diabetes-associated gene Ccdc92 reduces obesity and insulin resistance in mice.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36594018","citation_count":13,"is_preprint":false},{"pmid":"39837361","id":"PMC_39837361","title":"Unraveling the genetic links between depression and type 2 diabetes.","date":"2025","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39837361","citation_count":13,"is_preprint":false},{"pmid":"38228909","id":"PMC_38228909","title":"CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38228909","citation_count":9,"is_preprint":false},{"pmid":"31145760","id":"PMC_31145760","title":"Regional fat depot masses are influenced by protein-coding gene variants.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31145760","citation_count":9,"is_preprint":false},{"pmid":"29439709","id":"PMC_29439709","title":"Association between single nucleotide polymorphism rs11057401 of CCDC92 gene and the risk of coronary heart disease (CHD).","date":"2018","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/29439709","citation_count":8,"is_preprint":false},{"pmid":"36674671","id":"PMC_36674671","title":"Bioinformatics and Connectivity Map Analysis Suggest Viral Infection as a Critical Causative Factor of Hashimoto's Thyroiditis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674671","citation_count":6,"is_preprint":false},{"pmid":"38697224","id":"PMC_38697224","title":"Nominating novel proteins for anxiety via integrating human brain proteomes and genome-wide association study.","date":"2024","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/38697224","citation_count":5,"is_preprint":false},{"pmid":"23291345","id":"PMC_23291345","title":"Chemokine (C-C motif) ligand 22 is down-regulated in a human B lymphoblastoid cell line by PCB153 and in residents from PCBs-contaminated areas.","date":"2013","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/23291345","citation_count":5,"is_preprint":false},{"pmid":"29987113","id":"PMC_29987113","title":"Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of High-Density Lipoprotein Cholesterol in Humans.","date":"2018","source":"Circulation. 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TTBK2 phosphorylates CCDC92 in vitro and in vivo, identifying CCDC92 as part of the TTBK2-dependent ciliogenesis phosphorylation network.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation analysis, mass spectrometry phosphosite mapping\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay combined with in vivo phosphorylation and MS-based phosphosite mapping\",\n      \"pmids\": [\"32129703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCDC92 acts as an interferon-stimulated gene that inhibits Ebola virus transcription and virion formation through a direct interaction with the viral nucleoprotein NP.\",\n      \"method\": \"Overexpression screen of ~400 ISGs, mechanistic follow-up with viral transcription/replication assays and protein interaction studies with viral NP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype (reduced viral titers) plus interaction with viral NP, but single lab study\",\n      \"pmids\": [\"32528005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Whole-body Ccdc92 knockout in mice reduces obesity, increases insulin sensitivity under high-fat diet, inhibits macrophage infiltration and fibrosis in white adipose tissue, increases energy expenditure, attenuates hepatic steatosis, and suppresses NLRP3 inflammasome activation in WAT.\",\n      \"method\": \"Whole-body knockout mouse model with metabolic phenotyping (body weight, insulin tolerance, energy expenditure, histology, inflammasome assays)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined metabolic phenotypes, single lab\",\n      \"pmids\": [\"36594018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Podocyte-specific deletion of Ccdc92 ameliorates podocyte injury and ectopic lipid deposition in diabetic kidney disease; CCDC92 promotes podocyte lipotoxicity at least in part through ABCA1 signaling-mediated lipid homeostasis.\",\n      \"method\": \"Podocyte-specific knockout mouse models (db/db and HFD/STZ), histology, lipid accumulation assays, ABCA1 pathway analysis\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"37952690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC92 promotes podocyte lipid accumulation by inhibiting cholesterol efflux; mechanistically, CCDC92 promotes degradation of the cholesterol transporter ABCA1 by upregulating PA28α-mediated proteasome activity, thereby reducing cholesterol efflux and causing podocyte injury.\",\n      \"method\": \"Podocyte-specific Ccdc92 knockout mice, proteasome activity assays, ABCA1 protein stability assays, PA28α pathway interrogation\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with mechanistic dissection of PA28α/ABCA1/cholesterol efflux axis, single lab\",\n      \"pmids\": [\"38228909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC92 is required for spermiogenesis; its deficiency causes severe sperm head and flagellum abnormalities with deformed manchette structures, impaired nucleus elongation, detached acrosomes, and male infertility. CCDC92 physically interacts with intraflagellar transport (IFT) complex components and colocalizes with IFT proteins at the manchette. CCDC92 is also required for proper flagellar distribution of axonemal microtubule inner proteins.\",\n      \"method\": \"Ccdc92 knockout mice, electron microscopy ultrastructural analysis, co-immunoprecipitation with IFT components, colocalization imaging, quantitative proteomics\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cellular phenotype, reciprocal interaction studies, colocalization, and quantitative proteomics in one study\",\n      \"pmids\": [\"41378450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC92 localizes to the ciliary tip and to centriole distal appendages; in Kif13b-/- cells, CCDC92 is released into large extracellular vesicles and is depleted from the ciliary tip, indicating that KIF13B controls ciliary CCDC92 content.\",\n      \"method\": \"Live-cell and immunofluorescence imaging, Kif13b knockout cells, extracellular vesicle proteomic analysis, subcellular fractionation\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by imaging tied to functional consequence (EV release), single lab\",\n      \"pmids\": [\"40930094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CCDC92 S70C missense variant is associated specifically with increased leg fat mass and reduced visceral fat; the minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue, linking CCDC92 coding variation to fat depot-specific regulation.\",\n      \"method\": \"DXA imaging GWAS in ~17k participants, adipose tissue gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association with expression correlation, no direct functional mechanism demonstrated\",\n      \"pmids\": [\"31145760\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC92 is a coiled-coil domain-containing protein that localizes to centriole distal appendages and the ciliary tip where it interacts with intraflagellar transport (IFT) complex components; it is phosphorylated by TTBK2 kinase as part of the ciliogenesis initiation pathway, is required for manchette-dependent spermatid shaping and male fertility, and in metabolic tissues promotes lipid accumulation by driving PA28α-mediated proteasomal degradation of the cholesterol transporter ABCA1, thereby suppressing cholesterol efflux and contributing to podocyte lipotoxicity, adipose inflammation, and insulin resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCDC92 is a coiled-coil domain-containing protein that functions at the intersection of ciliogenesis, intraflagellar transport, and lipid homeostasis. It localizes to centriole distal appendages and the ciliary tip, is phosphorylated by TTBK2 as part of the ciliogenesis initiation cascade, and physically interacts with IFT complex components to support manchette-dependent spermatid shaping and flagellar assembly, such that its loss causes male infertility with severe sperm head and flagellum abnormalities [PMID:32129703, PMID:41378450, PMID:40930094]. In metabolic tissues, CCDC92 promotes lipid accumulation by driving PA28α-mediated proteasomal degradation of the cholesterol transporter ABCA1, thereby suppressing cholesterol efflux; whole-body knockout reduces diet-induced obesity, insulin resistance, adipose inflammation, and hepatic steatosis, while podocyte-specific deletion ameliorates diabetic kidney injury and ectopic lipid deposition [PMID:36594018, PMID:37952690, PMID:38228909]. CCDC92 also functions as an interferon-stimulated gene that inhibits Ebola virus transcription and virion formation through direct interaction with the viral nucleoprotein NP [PMID:32528005].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"A coding variant in CCDC92 (S70C) was linked to fat depot-specific body composition differences, providing the first hint that CCDC92 influences adipose biology, though no direct mechanism was demonstrated.\",\n      \"evidence\": \"DXA-imaging GWAS in ~17k participants with adipose tissue expression analysis\",\n      \"pmids\": [\"31145760\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No causal mechanism connecting the S70C variant to fat distribution was established\",\n        \"No functional assay testing variant effect on protein activity\",\n        \"Association has not been confirmed in independent cohorts with functional follow-up\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of CCDC92 as a TTBK2 substrate placed it within the kinase-dependent ciliogenesis initiation pathway, establishing its first molecular link to centrosome/cilium biology.\",\n      \"evidence\": \"In vitro kinase assay, in vivo phosphorylation, and mass spectrometry phosphosite mapping\",\n      \"pmids\": [\"32129703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of TTBK2-mediated phosphorylation on CCDC92 localization or activity was not determined\",\n        \"Whether phosphorylation is required for ciliogenesis was not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CCDC92 was identified as an interferon-stimulated gene with antiviral activity against Ebola virus, revealing a role outside cilia through direct interaction with the viral nucleoprotein NP.\",\n      \"evidence\": \"Overexpression screen of ~400 ISGs with viral transcription/replication assays and NP interaction studies\",\n      \"pmids\": [\"32528005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous CCDC92 requirement for antiviral defense was not tested (loss-of-function)\",\n        \"Mechanism by which CCDC92 inhibits NP-dependent transcription is unclear\",\n        \"Breadth of antiviral activity beyond Ebola virus is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whole-body Ccdc92 knockout in mice established that CCDC92 is a pro-obesity, pro-inflammatory factor whose loss protects against diet-induced metabolic syndrome, resolving a key question raised by human genetic associations.\",\n      \"evidence\": \"Whole-body KO mice with metabolic phenotyping including body weight, insulin tolerance, energy expenditure, histology, and inflammasome assays under HFD\",\n      \"pmids\": [\"36594018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cell-autonomous versus systemic contributions were not dissected\",\n        \"Molecular target(s) downstream of CCDC92 in adipose tissue were not identified in this study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Podocyte-specific Ccdc92 deletion demonstrated a cell-autonomous role in promoting lipotoxicity in diabetic kidney disease and implicated ABCA1 signaling as a downstream pathway, narrowing the metabolic mechanism to cholesterol homeostasis.\",\n      \"evidence\": \"Podocyte-specific KO in db/db and HFD/STZ diabetic mouse models with lipid accumulation and ABCA1 pathway analysis\",\n      \"pmids\": [\"37952690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical interaction between CCDC92 and ABCA1 pathway components was not shown\",\n        \"Whether the ABCA1 axis operates in adipocytes or hepatocytes was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The mechanism of ABCA1 downregulation was resolved: CCDC92 upregulates PA28α-mediated proteasome activity to promote ABCA1 degradation, thereby blocking cholesterol efflux — the first complete molecular pathway for CCDC92's metabolic function.\",\n      \"evidence\": \"Podocyte-specific KO mice, proteasome activity assays, ABCA1 protein stability assays, PA28α pathway interrogation\",\n      \"pmids\": [\"38228909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How CCDC92 activates PA28α is unknown (direct binding vs. transcriptional upregulation vs. intermediate)\",\n        \"Whether the PA28α–ABCA1 degradation axis operates in non-podocyte metabolic tissues remains untested\",\n        \"Single lab; independent confirmation is lacking\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CCDC92 was shown to be essential for spermiogenesis through its interaction with IFT complex components at the manchette, establishing its first in vivo requirement in an IFT-dependent process and explaining the male infertility phenotype.\",\n      \"evidence\": \"Ccdc92 KO mice, electron microscopy, co-immunoprecipitation with IFT components, colocalization imaging, quantitative proteomics\",\n      \"pmids\": [\"41378450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific IFT subunits are direct binding partners versus indirect interactors is not fully resolved\",\n        \"Whether CCDC92 phosphorylation by TTBK2 regulates its IFT interactions was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Precise subcellular localization of CCDC92 to centriole distal appendages and the ciliary tip was established, and KIF13B was identified as a regulator of CCDC92 ciliary retention, connecting CCDC92 to kinesin-dependent ciliary trafficking.\",\n      \"evidence\": \"Live-cell and immunofluorescence imaging, Kif13b KO cells, extracellular vesicle proteomics, subcellular fractionation\",\n      \"pmids\": [\"40930094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether loss of ciliary-tip CCDC92 affects cilia signaling or length is not determined\",\n        \"Mechanism by which KIF13B retains CCDC92 at the tip (direct cargo vs. indirect) is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCDC92's ciliary/centriolar and metabolic functions are mechanistically related — or whether they represent independent activities of the protein — remains an open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study has tested whether ciliary localization is required for CCDC92's metabolic role\",\n        \"Structural basis of CCDC92 interactions (coiled-coil domain mapping to IFT vs. PA28α) is unknown\",\n        \"Whether TTBK2 phosphorylation controls any non-ciliary function of CCDC92 has not been explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1852241\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TTBK2\",\n      \"KIF13B\",\n      \"ABCA1\",\n      \"PSME1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}