Affinage

CEP78

Centrosomal protein of 78 kDa · UniProt Q5JTW2

Length
689 aa
Mass
76.4 kDa
Annotated
2026-06-09
17 papers in source corpus 9 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2016 Medium

    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

    PMID:27246242

    Open questions at the time
    • 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
  2. 2016 Medium

    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

    PMID:27588451

    Open questions at the time
    • Functional significance of the FAM161A interaction not mechanistically defined
    • Does not establish the molecular pathway downstream of CEP78 loss
  3. 2017 High

    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

    PMID:28242748

    Open questions at the time
    • Structural basis of CEP78-VprBP recognition not determined
    • How CEP78's inhibitory activity is regulated in time/space is unknown
  4. 2020 Low

    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

    PMID:31999394

    Open questions at the time
    • 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
  5. 2021 High

    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

    PMID:34259627

    Open questions at the time
    • How CEP350 stabilizes CEP78 at the centrosome not mechanistically detailed
    • Quantitative contribution of EDD1 recruitment versus ligase inhibition not separated
  6. 2022 Medium

    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

    PMID:36206347

    Open questions at the time
    • Direct biochemical link between CEP78 and USP16 expression not established
    • Whether USP16/Tektin axis operates through the centriolar CP110 mechanism unclear
  7. 2023 Medium

    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

    PMID:36756949

    Open questions at the time
    • Single-lab Co-IP interactions without reciprocal structural mapping
    • How CEP78 controls IFT-protein stability mechanistically is undefined
  8. 2025 Low

    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)

    PMID:40777246

    Open questions at the time
    • Single Co-IP in a preprint without functional follow-up specific to CEP78
    • CAKUT disease link for CEP78 not independently validated
  9. 2025 Medium

    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

    PMID:39747485

    Open questions at the time
    • Transcriptomic changes not causally linked to the centriolar CP110 mechanism
    • Single-lab phenotypic characterization

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005929 cilium 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-1640170 Cell Cycle 1
Partners
CEP350CP110EDD1FAM161AIFT20PLK4TTC21AVPRBP

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 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. Co-immunoprecipitation, direct interaction studies, in vitro ubiquitination assay, subcellular fractionation/localization, loss-of-function perturbation with phenotypic readout (centriole length, cilia assembly) EMBO reports High 28242748
2021 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. 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 eLife High 34259627
2016 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. 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 of cell science Medium 27246242
2016 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. Immunostaining (subcellular localization in fibroblasts and human retina), co-immunoprecipitation/interaction studies (CEP78-FAM161A), patient fibroblast morphological analysis American journal of human genetics Medium 27588451
2022 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. Cep78 knockout mice, Western blotting for USP16 and Tektin protein levels, ubiquitination pathway analysis, intracytoplasmic sperm injection (negative rescue result) Science advances Medium 36206347
2023 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. Co-immunoprecipitation (CEP78-IFT20 and CEP78-TTC21A interactions), Cep78 knockout mice, immunofluorescence/electron microscopy for centriole and cilia structure, ERG for photoreceptor function eLife Medium 36756949
2020 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. Patient fibroblast analysis (protein stability by Western blot), cilia morphology assessment (immunofluorescence), homology modeling Human mutation Low 31999394
2025 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. Co-immunoprecipitation of CEP78 truncating variants vs. CEP350 and VPRBP bioRxivpreprint Low 40777246
2025 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. Co-immunoprecipitation/binding assay (importin α – CEP78 interaction), immunofluorescence localization, Xenopus loss-of-function (palmitoylation-deficient mutant) with kidney morphology and cilia phenotype readout bioRxivpreprint Low
2025 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. Cep78 knockout mice, histomorphology of germ cells, apoptotic assays, RNA-sequencing of testicular tissue Scientific reports Medium 39747485

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1VprBP. EMBO reports 48 28242748
2016 Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects. American journal of human genetics 46 27588451
2016 CEP78 is mutated in a distinct type of Usher syndrome. Journal of medical genetics 38 27627988
2022 Loss-of-function mutations in CEP78 cause male infertility in humans and mice. Science advances 35 36206347
2016 Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss. American journal of human genetics 34 27588452
2021 CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels. eLife 33 34259627
2016 Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication. Journal of cell science 23 27246242
2021 Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss. Frontiers in cell and developmental biology 19 33968938
2023 Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual. eLife 17 36756949
2020 Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility. Human mutation 17 31999394
2022 An association of CEP78, MEF2C, VPS13A and ARRDC3 genes with survivability to heat stress in an F2 chicken population. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 15 35218583
2022 A novel frameshift variant in CEP78 associated with nonsyndromic retinitis pigmentosa, and a review of CEP78-related phenotypes. Ophthalmic genetics 8 35240912
2025 Cep78 knockout causes sterility and oligoasthenoteratozoospermia in male mice. Scientific reports 4 39747485
2025 CAKUT variants in PRPF8, DYRK2, and CEP78: implications for splicing and ciliogenesis. bioRxiv : the preprint server for biology 1 40777246
2026 A novel CEP78 variant and rod-cone dystrophy in non-consanguineous siblings. Ophthalmic genetics 0 41991503
2026 Finding and computational analyses of a novel mutation in CEP78 linked to cone-rod dystrophy and hearing loss. Human molecular genetics 0 42234461
2024 Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series. American journal of medical genetics. Part A 0 38780195

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