{"gene":"CEP78","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2017,"finding":"CEP78 localizes to mature centrioles and directly interacts with VprBP, a component of the EDD-DYRK2-DDB1VprBP E3 ubiquitin ligase complex. CEP78 binds specifically to EDD-DYRK2-DDB1VprBP (not CRL4VprBP) and inhibits its activity by impeding the transfer of ubiquitin from EDD to CP110, without affecting CP110 phosphorylation by DYRK2 or CP110 binding to VprBP. This regulation controls CP110 ubiquitination and protein stability, thereby affecting centriole length and cilia assembly.","method":"Co-immunoprecipitation, direct interaction studies, in vitro ubiquitination assay, subcellular fractionation/localization, loss-of-function perturbation with phenotypic readout (centriole length, cilia assembly)","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, in vitro ubiquitination assay, localization, mutagenesis-level mechanistic dissection), single lab but rigorous mechanistic resolution of the enzymatic step inhibited","pmids":["28242748"],"is_preprint":false},{"year":2021,"finding":"CEP78 functions downstream of CEP350 in a pathway controlling ciliogenesis. CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn recruits EDD1 to the centrosome. CEP78-deficient cells display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restores ciliation frequency to normal, placing CEP78 upstream of CP110 in ciliogenesis via an EDD1-dependent mechanism. The disease-causing CEP78 p.L150S mutation weakens the CEP78-CEP350 interaction.","method":"Co-immunoprecipitation (confirmed CEP78-EDD1-DYRK2-DDB1VPRBP interaction; identified novel CEP78-CEP350 interaction), loss-of-function (CEP78 KO/depletion), rescue experiment (CP110 depletion in CEP78-deficient cells), quantitative immunofluorescence of CP110 levels, disease-variant functional analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for novel CEP350 interaction, epistasis rescue experiment, quantitative phenotypic readout, disease variant validation, multiple orthogonal methods in one study","pmids":["34259627"],"is_preprint":false},{"year":2016,"finding":"CEP78 is a centriolar protein that localizes to the centriolar wall and interacts with PLK4 through PLK4's N-terminal catalytic domain. CEP78 is required for PLK4-induced centriole overduplication, and upon CEP78 depletion, newly synthesized PLK4 fails to localize to centrosomes. CEP78 is not an in vitro PLK4 substrate.","method":"Co-immunoprecipitation (CEP78-PLK4 interaction), siRNA depletion with centriole overduplication assay, immunofluorescence localization, in vitro kinase assay (negative result for CEP78 phosphorylation by PLK4)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for interaction, loss-of-function with defined phenotype (centriole overduplication, PLK4 mislocalization), in vitro kinase assay; single lab, multiple methods","pmids":["27246242"],"is_preprint":false},{"year":2016,"finding":"CEP78 localizes to the base of the primary cilium in fibroblasts and to the inner segments of retinal photoreceptors (predominantly cones). CEP78 interacts with FAM161A, a ciliary protein associated with retinal degeneration. Loss-of-function mutations in CEP78 cause abnormal ciliary morphology in patient-derived skin fibroblasts.","method":"Immunostaining (subcellular localization in fibroblasts and human retina), co-immunoprecipitation/interaction studies (CEP78-FAM161A), patient fibroblast morphological analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiment with functional consequence (abnormal cilia in patient cells), Co-IP for FAM161A interaction; single lab","pmids":["27588451"],"is_preprint":false},{"year":2022,"finding":"CEP78 regulates USP16 expression, which in turn stabilizes Tektin levels via the ubiquitination pathway, linking CEP78 to sperm flagella integrity. CEP78 knockout mice display severely reduced sperm count, aberrant sperm morphology, and null sperm motility, as well as retinal and outer hair cell impairments.","method":"Cep78 knockout mice, Western blotting for USP16 and Tektin protein levels, ubiquitination pathway analysis, intracytoplasmic sperm injection (negative rescue result)","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KO mouse with defined cellular phenotype, mechanistic link to USP16/Tektin pathway proposed with protein-level evidence; single lab","pmids":["36206347"],"is_preprint":false},{"year":2023,"finding":"CEP78 interacts with intraflagellar transport proteins IFT20 and TTC21A. CEP78 regulates the interaction, stability, and centriolar localization of these interacting proteins. Insufficiency of CEP78 causes abnormal centriole elongation and cilia shortening. Cep78 knockout mice display disrupted translocation of cone arrestin, disorganized photoreceptor outer segment disks, widened outer segment bases, interrupted connecting cilia elongation, and disordered sperm axoneme ('9+2') structure.","method":"Co-immunoprecipitation (CEP78-IFT20 and CEP78-TTC21A interactions), Cep78 knockout mice, immunofluorescence/electron microscopy for centriole and cilia structure, ERG for photoreceptor function","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for novel interactors, KO mouse with multiple orthogonal phenotypic readouts (EM, ERG, immunofluorescence); single lab","pmids":["36756949"],"is_preprint":false},{"year":2020,"finding":"The CEP78 missense variant p.Leu150Ser reduces protein stability in patient fibroblasts and leads to elongated primary cilia, consistent with impaired cilia assembly. Homology modeling predicted a detrimental effect on protein stability, confirmed at the protein level in patient cells.","method":"Patient fibroblast analysis (protein stability by Western blot), cilia morphology assessment (immunofluorescence), homology modeling","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — patient fibroblast protein stability and cilia morphology, single lab, limited mechanistic depth; homology modeling is computational","pmids":["31999394"],"is_preprint":false},{"year":2025,"finding":"CEP78 truncating variants abrogate binding to both CEP350 and VPRBP, as demonstrated by co-immunoprecipitation in the context of CAKUT variant analysis. This confirms that disease-causing truncations disrupt CEP78's known protein interactions at the centrosome.","method":"Co-immunoprecipitation of CEP78 truncating variants vs. CEP350 and VPRBP","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment reported in preprint, no full mechanistic follow-up specific to CEP78","pmids":["40777246"],"is_preprint":true},{"year":2025,"finding":"Importin α binds CEP78 (along with CEP164 and ARL13B) at the base or lumen of primary and motile cilia, and is required for ciliogenesis initiation and cilia length maintenance. Disruption of importin α palmitoylation in Xenopus laevis leads to abnormal kidney morphology and reduced renal primary cilia.","method":"Co-immunoprecipitation/binding assay (importin α – CEP78 interaction), immunofluorescence localization, Xenopus loss-of-function (palmitoylation-deficient mutant) with kidney morphology and cilia phenotype readout","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single Co-IP for CEP78 interaction, CEP78 is one of several proteins listed; mechanistic role of CEP78 specifically is not independently validated","pmids":[],"is_preprint":true},{"year":2025,"finding":"CEP78 deficiency in Cep78 knockout mice causes defects in acrosomal biogenesis, sperm head shaping, and sperm flagella formation during spermiogenesis, resulting in oligoasthenoteratozoospermia and male sterility. RNA-sequencing of testicular tissue identified transcriptional changes associated with CEP78 loss.","method":"Cep78 knockout mice, histomorphology of germ cells, apoptotic assays, RNA-sequencing of testicular tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotypes (acrosome, sperm head, flagella) assessed by histomorphology and transcriptomics; single lab, multiple readouts","pmids":["39747485"],"is_preprint":false}],"current_model":"CEP78 is a centriolar protein that localizes to mature centrioles and functions as an inhibitor of the EDD-DYRK2-DDB1VprBP E3 ubiquitin ligase complex, blocking ubiquitin transfer to CP110 to regulate CP110 stability and thereby control centriole length and ciliogenesis; CEP78 itself is recruited and stabilized at the centrosome by CEP350, interacts with PLK4 to support centriole duplication, and engages IFT proteins (IFT20, TTC21A) and FAM161A to maintain ciliary structure, with loss of CEP78 causing cone-rod dystrophy, sensorineural hearing loss, and male infertility due to defects in photoreceptor connecting cilia and sperm flagella."},"narrative":{"mechanistic_narrative":"CEP78 is a centriolar protein that controls centriole length and ciliogenesis by acting as a negative regulator of CP110 ubiquitination at mature centrioles [PMID:28242748]. It localizes to the centriolar wall and to the base of the primary cilium, and binds VprBP within the EDD-DYRK2-DDB1VprBP E3 ubiquitin ligase complex, where it inhibits transfer of ubiquitin from EDD to CP110—without affecting CP110 phosphorylation by DYRK2 or its binding to VprBP—thereby stabilizing CP110 levels [PMID:28242748]. CEP78 itself is recruited to and stabilized at the centrosome by CEP350, and it in turn recruits EDD1; loss of CEP78 elevates cellular and centrosomal CP110, and depleting CP110 in CEP78-deficient cells restores ciliation, placing CEP78 upstream of CP110 in ciliogenesis [PMID:34259627]. CEP78 additionally interacts with PLK4 through PLK4's N-terminal catalytic domain and is required for PLK4 recruitment to centrosomes and PLK4-induced centriole overduplication, although it is not itself a PLK4 substrate [PMID:27246242]. Through interactions with intraflagellar transport proteins IFT20 and TTC21A, whose stability and centriolar localization it regulates, CEP78 supports proper centriole elongation and cilia length [PMID:36756949]. In vivo, Cep78 loss produces defects in photoreceptor connecting cilia and outer segments, outer hair cells, and sperm flagella and acrosome biogenesis, causing oligoasthenoteratozoospermia and male sterility [PMID:36756949, PMID:39747485]; consistent with a human disease role, a CEP78 missense variant (p.Leu150Ser) reduces protein stability and weakens the CEP78-CEP350 interaction, yielding abnormal cilia [PMID:34259627, PMID:31999394].","teleology":[{"year":2016,"claim":"Established that CEP78 is a centriolar wall protein physically and functionally linked to the master centriole duplication kinase PLK4, addressing how CEP78 participates in centriole biogenesis.","evidence":"Co-IP mapping CEP78 to PLK4's N-terminal catalytic domain, siRNA depletion with centriole overduplication assay, and in vitro kinase assay in human cells","pmids":["27246242"],"confidence":"Medium","gaps":["Mechanism by which CEP78 promotes PLK4 centrosomal recruitment not resolved","Single lab, Co-IP-based interaction without structural detail","Does not connect PLK4 role to CEP78's CP110 regulation"]},{"year":2016,"claim":"Connected CEP78 to ciliary biology and human retinal disease by localizing it to the cilium base and photoreceptor inner segments and identifying FAM161A as an interactor.","evidence":"Immunostaining in fibroblasts and human retina, Co-IP for CEP78-FAM161A, and morphological analysis of patient fibroblasts","pmids":["27588451"],"confidence":"Medium","gaps":["Functional significance of the FAM161A interaction not mechanistically defined","Does not establish the molecular pathway downstream of CEP78 loss"]},{"year":2017,"claim":"Defined the core molecular mechanism: CEP78 inhibits the EDD-DYRK2-DDB1VprBP ligase to block CP110 ubiquitination, providing a direct biochemical basis for centriole-length and cilia control.","evidence":"Co-IP, direct interaction studies, in vitro ubiquitination assay, and loss-of-function with centriole-length/cilia readouts","pmids":["28242748"],"confidence":"High","gaps":["Structural basis of CEP78-VprBP recognition not determined","How CEP78's inhibitory activity is regulated in time/space is unknown"]},{"year":2020,"claim":"Demonstrated a disease-variant mechanism by showing the p.Leu150Ser substitution destabilizes CEP78 and produces elongated cilia, linking loss of protein to a ciliary phenotype.","evidence":"Patient fibroblast Western blot for protein stability, cilia morphology by immunofluorescence, and homology modeling","pmids":["31999394"],"confidence":"Low","gaps":["Homology modeling is computational; structural effect inferred not measured","Single-variant, single-lab analysis without rescue","Does not directly tie stability loss to CP110 dysregulation"]},{"year":2021,"claim":"Placed CEP78 within an ordered pathway by showing CEP350 recruits and stabilizes CEP78, which recruits EDD1, and that CP110 depletion rescues ciliation in CEP78-deficient cells, establishing CEP78 epistatically upstream of CP110.","evidence":"Reciprocal Co-IP for CEP78-CEP350, KO/depletion, CP110-depletion rescue, quantitative CP110 immunofluorescence, and disease-variant analysis","pmids":["34259627"],"confidence":"High","gaps":["How CEP350 stabilizes CEP78 at the centrosome not mechanistically detailed","Quantitative contribution of EDD1 recruitment versus ligase inhibition not separated"]},{"year":2022,"claim":"Extended CEP78's role to sperm flagella by proposing a CEP78-USP16-Tektin axis and demonstrating severe spermatogenic and sensory phenotypes in knockout mice.","evidence":"Cep78 knockout mice, Western blotting for USP16 and Tektin, ubiquitination pathway analysis, and ICSI rescue testing","pmids":["36206347"],"confidence":"Medium","gaps":["Direct biochemical link between CEP78 and USP16 expression not established","Whether USP16/Tektin axis operates through the centriolar CP110 mechanism unclear"]},{"year":2023,"claim":"Identified IFT20 and TTC21A as CEP78 interactors whose stability and localization it regulates, mechanistically connecting CEP78 to intraflagellar transport and ciliary structural integrity in vivo.","evidence":"Co-IP for CEP78-IFT20 and CEP78-TTC21A, Cep78 knockout mice, immunofluorescence/EM of centriole and cilia structure, and ERG","pmids":["36756949"],"confidence":"Medium","gaps":["Single-lab Co-IP interactions without reciprocal structural mapping","How CEP78 controls IFT-protein stability mechanistically is undefined"]},{"year":2025,"claim":"Reinforced the genotype-phenotype logic by showing truncating CEP78 variants abolish binding to both CEP350 and VPRBP in a CAKUT context.","evidence":"Co-IP of CEP78 truncating variants against CEP350 and VPRBP (preprint)","pmids":["40777246"],"confidence":"Low","gaps":["Single Co-IP in a preprint without functional follow-up specific to CEP78","CAKUT disease link for CEP78 not independently validated"]},{"year":2025,"claim":"Detailed the spermiogenesis defects of CEP78 loss—acrosomal, head-shaping, and flagellar—establishing CEP78 as required for male fertility and identifying associated testicular transcriptional changes.","evidence":"Cep78 knockout mice, germ-cell histomorphology, apoptotic assays, and testicular RNA-sequencing","pmids":["39747485"],"confidence":"Medium","gaps":["Transcriptomic changes not causally linked to the centriolar CP110 mechanism","Single-lab phenotypic characterization"]},{"year":null,"claim":"It remains unresolved how CEP78's centriolar CP110-regulatory mechanism is integrated with its proposed USP16/Tektin and IFT-stabilizing roles, and what structural features govern its interactions with CEP350, VprBP, and PLK4.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CEP78 or its interaction interfaces","No unifying mechanism connecting tissue-specific phenotypes to the core ligase-inhibition function","Regulation of CEP78 activity across the cell cycle unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["VPRBP","EDD1","CEP350","PLK4","FAM161A","IFT20","TTC21A","CP110"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5JTW2","full_name":"Centrosomal protein of 78 kDa","aliases":[],"length_aa":689,"mass_kda":76.4,"function":"Centriole wall protein that localizes to mature centrioles and regulates centriole and cilia biogenesis (PubMed:27246242, PubMed:27588451, PubMed:28242748, PubMed:34259627). Involved in centrosome duplication: required for efficient PLK4 centrosomal localization and PLK4-induced overduplication of centrioles (PubMed:27246242). Involved in cilium biogenesis and controls cilium length (PubMed:27588451). Acts as a regulator of protein stability by preventing ubiquitination of centrosomal proteins, such as CCP110 and tektins (PubMed:28242748, PubMed:34259627). Associates with the EDVP complex, preventing ubiquitination and degradation of CCP110 (PubMed:28242748, PubMed:34259627). Promotes deubiquitination of tektin proteins (TEKT1, TEKT2, TEK3, TEKT4 and TEKT5) via its interaction with USP16 (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q5JTW2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP78","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000148019","cell_line_id":"CID000193","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"MLEC","stoichiometry":0.2},{"gene":"NAP1L4","stoichiometry":0.2},{"gene":"STT3A","stoichiometry":0.2},{"gene":"FGFR1OP","stoichiometry":0.2},{"gene":"CTNNB1","stoichiometry":0.2},{"gene":"DDB1","stoichiometry":0.2},{"gene":"IPO5","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"SLC7A6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000193","total_profiled":1310},"omim":[{"mim_id":"618358","title":"CONE-ROD DYSTROPHY AND HEARING LOSS 2; CRDHL2","url":"https://www.omim.org/entry/618358"},{"mim_id":"617236","title":"CONE-ROD DYSTROPHY AND HEARING LOSS 1; CRDHL1","url":"https://www.omim.org/entry/617236"},{"mim_id":"617110","title":"CENTROSOMAL PROTEIN, 78-KD; CEP78","url":"https://www.omim.org/entry/617110"},{"mim_id":"609689","title":"CENTROSOMAL PROTEIN, 250-KD; CEP250","url":"https://www.omim.org/entry/609689"},{"mim_id":"605031","title":"POLO-LIKE KINASE 4; PLK4","url":"https://www.omim.org/entry/605031"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP78"},"hgnc":{"alias_symbol":["FLJ12643"],"prev_symbol":["C9orf81"]},"alphafold":{"accession":"Q5JTW2","domains":[{"cath_id":"3.80.10.10","chopping":"42-52_70-81_93-324","consensus_level":"medium","plddt":87.2836,"start":42,"end":324},{"cath_id":"1.20.5","chopping":"470-534","consensus_level":"medium","plddt":86.4505,"start":470,"end":534}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JTW2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JTW2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JTW2-F1-predicted_aligned_error_v6.png","plddt_mean":64.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP78","jax_strain_url":"https://www.jax.org/strain/search?query=CEP78"},"sequence":{"accession":"Q5JTW2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5JTW2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5JTW2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JTW2"}},"corpus_meta":[{"pmid":"28242748","id":"PMC_28242748","title":"Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1VprBP.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28242748","citation_count":48,"is_preprint":false},{"pmid":"27588451","id":"PMC_27588451","title":"Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27588451","citation_count":46,"is_preprint":false},{"pmid":"27627988","id":"PMC_27627988","title":"CEP78 is mutated in a distinct type of Usher syndrome.","date":"2016","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27627988","citation_count":38,"is_preprint":false},{"pmid":"36206347","id":"PMC_36206347","title":"Loss-of-function mutations in CEP78 cause male infertility in humans and mice.","date":"2022","source":"Science 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mutation","url":"https://pubmed.ncbi.nlm.nih.gov/31999394","citation_count":17,"is_preprint":false},{"pmid":"35218583","id":"PMC_35218583","title":"An association of CEP78, MEF2C, VPS13A and ARRDC3 genes with survivability to heat stress in an F2 chicken population.","date":"2022","source":"Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie","url":"https://pubmed.ncbi.nlm.nih.gov/35218583","citation_count":15,"is_preprint":false},{"pmid":"35240912","id":"PMC_35240912","title":"A novel frameshift variant in CEP78 associated with nonsyndromic retinitis pigmentosa, and a review of CEP78-related phenotypes.","date":"2022","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35240912","citation_count":8,"is_preprint":false},{"pmid":"39747485","id":"PMC_39747485","title":"Cep78 knockout causes sterility and oligoasthenoteratozoospermia in male mice.","date":"2025","source":"Scientific 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38780195","citation_count":0,"is_preprint":false},{"pmid":"41991503","id":"PMC_41991503","title":"A novel CEP78 variant and rod-cone dystrophy in non-consanguineous siblings.","date":"2026","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41991503","citation_count":0,"is_preprint":false},{"pmid":"42234461","id":"PMC_42234461","title":"Finding and computational analyses of a novel mutation in CEP78 linked to cone-rod dystrophy and hearing loss.","date":"2026","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/42234461","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.16.665151","title":"CAKUT variants in  <i>PRPF8, DYRK2</i>  , and  <i>CEP78</i>  : implications for splicing and ciliogenesis","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.665151","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.10.648263","title":"A Role for Importin α in Ciliogenesis and Cilia Length Regulation during Nephrogenesis","date":"2025-04-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.10.648263","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12067,"output_tokens":2947,"usd":0.040203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10289,"output_tokens":3600,"usd":0.070722,"stage2_stop_reason":"end_turn"},"total_usd":0.110925,"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\": 2017,\n      \"finding\": \"CEP78 localizes to mature centrioles and directly interacts with VprBP, a component of the EDD-DYRK2-DDB1VprBP E3 ubiquitin ligase complex. CEP78 binds specifically to EDD-DYRK2-DDB1VprBP (not CRL4VprBP) and inhibits its activity by impeding the transfer of ubiquitin from EDD to CP110, without affecting CP110 phosphorylation by DYRK2 or CP110 binding to VprBP. This regulation controls CP110 ubiquitination and protein stability, thereby affecting centriole length and cilia assembly.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction studies, in vitro ubiquitination assay, subcellular fractionation/localization, loss-of-function perturbation with phenotypic readout (centriole length, cilia assembly)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, in vitro ubiquitination assay, localization, mutagenesis-level mechanistic dissection), single lab but rigorous mechanistic resolution of the enzymatic step inhibited\",\n      \"pmids\": [\"28242748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP78 functions downstream of CEP350 in a pathway controlling ciliogenesis. CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn recruits EDD1 to the centrosome. CEP78-deficient cells display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restores ciliation frequency to normal, placing CEP78 upstream of CP110 in ciliogenesis via an EDD1-dependent mechanism. The disease-causing CEP78 p.L150S mutation weakens the CEP78-CEP350 interaction.\",\n      \"method\": \"Co-immunoprecipitation (confirmed CEP78-EDD1-DYRK2-DDB1VPRBP interaction; identified novel CEP78-CEP350 interaction), loss-of-function (CEP78 KO/depletion), rescue experiment (CP110 depletion in CEP78-deficient cells), quantitative immunofluorescence of CP110 levels, disease-variant functional analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for novel CEP350 interaction, epistasis rescue experiment, quantitative phenotypic readout, disease variant validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34259627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CEP78 is a centriolar protein that localizes to the centriolar wall and interacts with PLK4 through PLK4's N-terminal catalytic domain. CEP78 is required for PLK4-induced centriole overduplication, and upon CEP78 depletion, newly synthesized PLK4 fails to localize to centrosomes. CEP78 is not an in vitro PLK4 substrate.\",\n      \"method\": \"Co-immunoprecipitation (CEP78-PLK4 interaction), siRNA depletion with centriole overduplication assay, immunofluorescence localization, in vitro kinase assay (negative result for CEP78 phosphorylation by PLK4)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for interaction, loss-of-function with defined phenotype (centriole overduplication, PLK4 mislocalization), in vitro kinase assay; single lab, multiple methods\",\n      \"pmids\": [\"27246242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CEP78 localizes to the base of the primary cilium in fibroblasts and to the inner segments of retinal photoreceptors (predominantly cones). CEP78 interacts with FAM161A, a ciliary protein associated with retinal degeneration. Loss-of-function mutations in CEP78 cause abnormal ciliary morphology in patient-derived skin fibroblasts.\",\n      \"method\": \"Immunostaining (subcellular localization in fibroblasts and human retina), co-immunoprecipitation/interaction studies (CEP78-FAM161A), patient fibroblast morphological analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiment with functional consequence (abnormal cilia in patient cells), Co-IP for FAM161A interaction; single lab\",\n      \"pmids\": [\"27588451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP78 regulates USP16 expression, which in turn stabilizes Tektin levels via the ubiquitination pathway, linking CEP78 to sperm flagella integrity. CEP78 knockout mice display severely reduced sperm count, aberrant sperm morphology, and null sperm motility, as well as retinal and outer hair cell impairments.\",\n      \"method\": \"Cep78 knockout mice, Western blotting for USP16 and Tektin protein levels, ubiquitination pathway analysis, intracytoplasmic sperm injection (negative rescue result)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KO mouse with defined cellular phenotype, mechanistic link to USP16/Tektin pathway proposed with protein-level evidence; single lab\",\n      \"pmids\": [\"36206347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEP78 interacts with intraflagellar transport proteins IFT20 and TTC21A. CEP78 regulates the interaction, stability, and centriolar localization of these interacting proteins. Insufficiency of CEP78 causes abnormal centriole elongation and cilia shortening. Cep78 knockout mice display disrupted translocation of cone arrestin, disorganized photoreceptor outer segment disks, widened outer segment bases, interrupted connecting cilia elongation, and disordered sperm axoneme ('9+2') structure.\",\n      \"method\": \"Co-immunoprecipitation (CEP78-IFT20 and CEP78-TTC21A interactions), Cep78 knockout mice, immunofluorescence/electron microscopy for centriole and cilia structure, ERG for photoreceptor function\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for novel interactors, KO mouse with multiple orthogonal phenotypic readouts (EM, ERG, immunofluorescence); single lab\",\n      \"pmids\": [\"36756949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CEP78 missense variant p.Leu150Ser reduces protein stability in patient fibroblasts and leads to elongated primary cilia, consistent with impaired cilia assembly. Homology modeling predicted a detrimental effect on protein stability, confirmed at the protein level in patient cells.\",\n      \"method\": \"Patient fibroblast analysis (protein stability by Western blot), cilia morphology assessment (immunofluorescence), homology modeling\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — patient fibroblast protein stability and cilia morphology, single lab, limited mechanistic depth; homology modeling is computational\",\n      \"pmids\": [\"31999394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CEP78 truncating variants abrogate binding to both CEP350 and VPRBP, as demonstrated by co-immunoprecipitation in the context of CAKUT variant analysis. This confirms that disease-causing truncations disrupt CEP78's known protein interactions at the centrosome.\",\n      \"method\": \"Co-immunoprecipitation of CEP78 truncating variants vs. CEP350 and VPRBP\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment reported in preprint, no full mechanistic follow-up specific to CEP78\",\n      \"pmids\": [\"40777246\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Importin α binds CEP78 (along with CEP164 and ARL13B) at the base or lumen of primary and motile cilia, and is required for ciliogenesis initiation and cilia length maintenance. Disruption of importin α palmitoylation in Xenopus laevis leads to abnormal kidney morphology and reduced renal primary cilia.\",\n      \"method\": \"Co-immunoprecipitation/binding assay (importin α – CEP78 interaction), immunofluorescence localization, Xenopus loss-of-function (palmitoylation-deficient mutant) with kidney morphology and cilia phenotype readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single Co-IP for CEP78 interaction, CEP78 is one of several proteins listed; mechanistic role of CEP78 specifically is not independently validated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CEP78 deficiency in Cep78 knockout mice causes defects in acrosomal biogenesis, sperm head shaping, and sperm flagella formation during spermiogenesis, resulting in oligoasthenoteratozoospermia and male sterility. RNA-sequencing of testicular tissue identified transcriptional changes associated with CEP78 loss.\",\n      \"method\": \"Cep78 knockout mice, histomorphology of germ cells, apoptotic assays, RNA-sequencing of testicular tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotypes (acrosome, sperm head, flagella) assessed by histomorphology and transcriptomics; single lab, multiple readouts\",\n      \"pmids\": [\"39747485\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP78 is a centriolar protein that localizes to mature centrioles and functions as an inhibitor of the EDD-DYRK2-DDB1VprBP E3 ubiquitin ligase complex, blocking ubiquitin transfer to CP110 to regulate CP110 stability and thereby control centriole length and ciliogenesis; CEP78 itself is recruited and stabilized at the centrosome by CEP350, interacts with PLK4 to support centriole duplication, and engages IFT proteins (IFT20, TTC21A) and FAM161A to maintain ciliary structure, with loss of CEP78 causing cone-rod dystrophy, sensorineural hearing loss, and male infertility due to defects in photoreceptor connecting cilia and sperm flagella.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEP78 is a centriolar protein that controls centriole length and ciliogenesis by acting as a negative regulator of CP110 ubiquitination at mature centrioles [#0]. It localizes to the centriolar wall and to the base of the primary cilium, and binds VprBP within the EDD-DYRK2-DDB1VprBP E3 ubiquitin ligase complex, where it inhibits transfer of ubiquitin from EDD to CP110—without affecting CP110 phosphorylation by DYRK2 or its binding to VprBP—thereby stabilizing CP110 levels [#0]. CEP78 itself is recruited to and stabilized at the centrosome by CEP350, and it in turn recruits EDD1; loss of CEP78 elevates cellular and centrosomal CP110, and depleting CP110 in CEP78-deficient cells restores ciliation, placing CEP78 upstream of CP110 in ciliogenesis [#1]. CEP78 additionally interacts with PLK4 through PLK4's N-terminal catalytic domain and is required for PLK4 recruitment to centrosomes and PLK4-induced centriole overduplication, although it is not itself a PLK4 substrate [#2]. Through interactions with intraflagellar transport proteins IFT20 and TTC21A, whose stability and centriolar localization it regulates, CEP78 supports proper centriole elongation and cilia length [#5]. In vivo, Cep78 loss produces defects in photoreceptor connecting cilia and outer segments, outer hair cells, and sperm flagella and acrosome biogenesis, causing oligoasthenoteratozoospermia and male sterility [#5, #9]; consistent with a human disease role, a CEP78 missense variant (p.Leu150Ser) reduces protein stability and weakens the CEP78-CEP350 interaction, yielding abnormal cilia [#1, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that CEP78 is a centriolar wall protein physically and functionally linked to the master centriole duplication kinase PLK4, addressing how CEP78 participates in centriole biogenesis.\",\n      \"evidence\": \"Co-IP mapping CEP78 to PLK4's N-terminal catalytic domain, siRNA depletion with centriole overduplication assay, and in vitro kinase assay in human cells\",\n      \"pmids\": [\"27246242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CEP78 promotes PLK4 centrosomal recruitment not resolved\",\n        \"Single lab, Co-IP-based interaction without structural detail\",\n        \"Does not connect PLK4 role to CEP78's CP110 regulation\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CEP78 to ciliary biology and human retinal disease by localizing it to the cilium base and photoreceptor inner segments and identifying FAM161A as an interactor.\",\n      \"evidence\": \"Immunostaining in fibroblasts and human retina, Co-IP for CEP78-FAM161A, and morphological analysis of patient fibroblasts\",\n      \"pmids\": [\"27588451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of the FAM161A interaction not mechanistically defined\",\n        \"Does not establish the molecular pathway downstream of CEP78 loss\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the core molecular mechanism: CEP78 inhibits the EDD-DYRK2-DDB1VprBP ligase to block CP110 ubiquitination, providing a direct biochemical basis for centriole-length and cilia control.\",\n      \"evidence\": \"Co-IP, direct interaction studies, in vitro ubiquitination assay, and loss-of-function with centriole-length/cilia readouts\",\n      \"pmids\": [\"28242748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of CEP78-VprBP recognition not determined\",\n        \"How CEP78's inhibitory activity is regulated in time/space is unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a disease-variant mechanism by showing the p.Leu150Ser substitution destabilizes CEP78 and produces elongated cilia, linking loss of protein to a ciliary phenotype.\",\n      \"evidence\": \"Patient fibroblast Western blot for protein stability, cilia morphology by immunofluorescence, and homology modeling\",\n      \"pmids\": [\"31999394\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Homology modeling is computational; structural effect inferred not measured\",\n        \"Single-variant, single-lab analysis without rescue\",\n        \"Does not directly tie stability loss to CP110 dysregulation\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed CEP78 within an ordered pathway by showing CEP350 recruits and stabilizes CEP78, which recruits EDD1, and that CP110 depletion rescues ciliation in CEP78-deficient cells, establishing CEP78 epistatically upstream of CP110.\",\n      \"evidence\": \"Reciprocal Co-IP for CEP78-CEP350, KO/depletion, CP110-depletion rescue, quantitative CP110 immunofluorescence, and disease-variant analysis\",\n      \"pmids\": [\"34259627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CEP350 stabilizes CEP78 at the centrosome not mechanistically detailed\",\n        \"Quantitative contribution of EDD1 recruitment versus ligase inhibition not separated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended CEP78's role to sperm flagella by proposing a CEP78-USP16-Tektin axis and demonstrating severe spermatogenic and sensory phenotypes in knockout mice.\",\n      \"evidence\": \"Cep78 knockout mice, Western blotting for USP16 and Tektin, ubiquitination pathway analysis, and ICSI rescue testing\",\n      \"pmids\": [\"36206347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical link between CEP78 and USP16 expression not established\",\n        \"Whether USP16/Tektin axis operates through the centriolar CP110 mechanism unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified IFT20 and TTC21A as CEP78 interactors whose stability and localization it regulates, mechanistically connecting CEP78 to intraflagellar transport and ciliary structural integrity in vivo.\",\n      \"evidence\": \"Co-IP for CEP78-IFT20 and CEP78-TTC21A, Cep78 knockout mice, immunofluorescence/EM of centriole and cilia structure, and ERG\",\n      \"pmids\": [\"36756949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab Co-IP interactions without reciprocal structural mapping\",\n        \"How CEP78 controls IFT-protein stability mechanistically is undefined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reinforced the genotype-phenotype logic by showing truncating CEP78 variants abolish binding to both CEP350 and VPRBP in a CAKUT context.\",\n      \"evidence\": \"Co-IP of CEP78 truncating variants against CEP350 and VPRBP (preprint)\",\n      \"pmids\": [\"40777246\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP in a preprint without functional follow-up specific to CEP78\",\n        \"CAKUT disease link for CEP78 not independently validated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed the spermiogenesis defects of CEP78 loss—acrosomal, head-shaping, and flagellar—establishing CEP78 as required for male fertility and identifying associated testicular transcriptional changes.\",\n      \"evidence\": \"Cep78 knockout mice, germ-cell histomorphology, apoptotic assays, and testicular RNA-sequencing\",\n      \"pmids\": [\"39747485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcriptomic changes not causally linked to the centriolar CP110 mechanism\",\n        \"Single-lab phenotypic characterization\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CEP78's centriolar CP110-regulatory mechanism is integrated with its proposed USP16/Tektin and IFT-stabilizing roles, and what structural features govern its interactions with CEP350, VprBP, and PLK4.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of CEP78 or its interaction interfaces\",\n        \"No unifying mechanism connecting tissue-specific phenotypes to the core ligase-inhibition function\",\n        \"Regulation of CEP78 activity across the cell cycle unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005814\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VprBP\", \"EDD1\", \"CEP350\", \"PLK4\", \"FAM161A\", \"IFT20\", \"TTC21A\", \"CP110\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}