CCDC92

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).

1. 2019 Low

   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

   PMID:31145760

   Open questions at the time

   • 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
2. 2020 High

   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

   PMID:32129703

   Open questions at the time

   • Functional consequence of TTBK2-mediated phosphorylation on CCDC92 localization or activity was not determined
   • Whether phosphorylation is required for ciliogenesis was not tested
3. 2020 Medium

   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

   PMID:32528005

   Open questions at the time

   • 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
4. 2022 Medium

   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

   PMID:36594018

   Open questions at the time

   • Cell-autonomous versus systemic contributions were not dissected
   • Molecular target(s) downstream of CCDC92 in adipose tissue were not identified in this study
5. 2023 Medium

   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

   PMID:37952690

   Open questions at the time

   • Direct biochemical interaction between CCDC92 and ABCA1 pathway components was not shown
   • Whether the ABCA1 axis operates in adipocytes or hepatocytes was not tested
6. 2024 Medium

   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

   PMID:38228909

   Open questions at the time

   • 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
7. 2025 High

   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

   PMID:41378450

   Open questions at the time

   • 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
8. 2025 Medium

   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

   PMID:40930094

   Open questions at the time

   • 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

• How CCDC92's ciliary/centriolar and metabolic functions are mechanistically related — or whether they represent independent activities of the protein — remains an open question.
• 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