CFAP263

CFAP263/CCDC113 is an evolutionarily conserved coiled-coil adaptor protein that organizes the axonemal machinery governing ciliary and flagellar motility (PMID:33661892, PMID:39671309). In cilia it forms an evolutionarily conserved complex with CCDC96 positioned parallel to the nexin-dynein regulatory complex (N-DRC), physically linking radial spoke 3 to dynein g and the N-DRC; its stable docking requires co-presence of CCDC96, and its loss alters ciliary beat frequency, amplitude, and waveform (PMID:33661892). In mouse sperm it serves the analogous adaptor role, binding CFAP57 and CFAP91 to connect radial spokes, the N-DRC, and doublet microtubules, and additionally acts as a structural component of the head-tail coupling apparatus together with SUN5 and CENTLEIN to join the sperm head to the flagellum during spermiogenesis (PMID:39671309). Loss of CCDC113 produces disorganized flagella and head-tail coupling defects, and biallelic loss-of-function mutations cause oligoasthenoteratozoospermia and male infertility in humans, recapitulated in knockout mice (PMID:39671309, PMID:41645397). In cultured somatic cells CCDC113 localizes to centriolar satellites in a complex with HAP1 and PCM1 and is required for primary cilium formation (PMID:25074808). A distinct role in promoting colorectal cancer cell proliferation and migration via TGF-β signaling has also been reported (PMID:39261464).

1. 2014 Medium

   Identifying CCDC113 at centriolar satellites and in complex with established satellite proteins placed it within the ciliogenesis machinery of somatic cells before its axonemal role was known.

   Evidence Mass spectrometry of sperm centrioles, immunofluorescence, reciprocal Co-IP with HAP1 and PCM1, and loss-of-function assay for cilium formation in cultured cells

   PMID:25074808

   Open questions at the time

   • Did not define the molecular function of the protein within the satellite complex
   • Mechanism by which it supports cilium assembly not resolved
   • No axonemal structural role established at this stage
2. 2021 High

   Genetic and structural dissection in ciliate/algal models established CCDC113 as a structural adaptor wiring radial spoke 3 to dynein g and the N-DRC, defining how it regulates beat pattern.

   Evidence Genetic deletion, axonemal structural analysis, ciliary beat frequency/waveform measurements, and CCDC113/CCDC96 epistasis

   PMID:33661892

   Open questions at the time

   • Atomic-resolution structure of the CCDC113-CCDC96 complex not determined
   • Mechanism linking the structural connection to specific waveform changes not detailed
   • Conservation of the role in mammalian sperm not yet tested at this point
3. 2024 High

   A knockout mouse and binding studies extended the adaptor role to sperm and revealed a second function in the head-tail coupling apparatus, connecting axonemal organization to whole-flagellum and head-tail integrity.

   Evidence Co-IP mapping binding to CFAP57, CFAP91, SUN5, and CENTLEIN; knockout mouse; TEM ultrastructure; fertility assays

   PMID:39671309

   Open questions at the time

   • Whether CCDC96 partnership is conserved in mammalian sperm not addressed
   • Stoichiometry and direct vs indirect nature of HTCA interactions not resolved
   • How the two roles (axoneme vs HTCA) are temporally coordinated unclear
4. 2024 Medium

   A reported cancer phenotype linked CCDC113 to TGF-β signaling in a context distinct from its ciliary structural role.

   Evidence RNA-seq, TCGA analysis, overexpression/knockdown in CRC lines, in vitro and in vivo tumor assays, and galunisertib rescue

   PMID:39261464

   Open questions at the time

   • Direct molecular link between CCDC113 and TGF-β pathway components not defined
   • Relationship to its ciliary/centriolar function unexplained
   • Single-lab finding without orthogonal mechanistic validation
5. 2026 Medium

   Human genetics confirmed CCDC113 as a disease gene, tying loss-of-function and reduced protein stability to oligoasthenoteratozoospermia.

   Evidence Whole-exome sequencing of patients, protein stability analysis of variants, and knockout mouse recapitulation with sperm morphology/motility and ultrastructural assays

   PMID:41645397

   Open questions at the time

   • Genotype-phenotype correlation across additional patients limited
   • Mechanism by which point mutations destabilize the protein not detailed
   • Single-lab cohort

• How CCDC113's conserved axonemal adaptor function relates mechanistically to its reported somatic and oncogenic roles remains unresolved.
• No high-resolution structure of CCDC113 in any complex
• Unclear whether the centriolar-satellite and axonemal roles share a common molecular activity
• Mechanistic basis of the TGF-β connection unestablished