CYLC1

CYLC1 (Cylicin 1) is a testis-specific structural protein of the sperm calyx within the perinuclear theca, where it is required for proper calyx assembly during spermiogenesis and for normal sperm head morphogenesis (PMID:38013430). Cylicin-1 self-associates and bridges the inner acrosomal membrane to the nuclear envelope by interacting with the IAM protein SPACA1 and the NE protein FAM209, forming an 'IAM-cylicins-NE' sandwich structure that physically anchors the acrosome to the sperm nucleus (PMID:38573307). Loss of Cylicin-1 in mice disrupts calyx assembly and detaches the acrosome from the nucleus, producing malformed sperm heads, impaired cytoplasmic shedding, reduced epididymal sperm counts, and defective motility, resulting in male subfertility (PMID:38013430, PMID:38573307). In humans, CYLC1 missense variants do not alter protein abundance but mislocalize the protein and disrupt acrosome morphology and the distribution of the sperm factor PLCZ1, linking CYLC1 dysfunction to male infertility (PMID:41075067).

1. 2023 High

   Established that CYLC1 is a structural component of the sperm calyx whose loss disrupts perinuclear theca assembly, defining its role in spermiogenesis and male fertility.

   Evidence CRISPR/Cas9 Cylc1 knockout mouse with immunofluorescence, electron microscopy, and fertility assays

   PMID:38013430

   Open questions at the time

   • Did not define the molecular binding partners that recruit Cylicin-1 to the calyx
   • Subfertility rather than complete sterility leaves the requirement incompletely defined
2. 2024 High

   Resolved how CYLC1 anchors the acrosome to the nucleus by identifying an IAM-cylicins-NE sandwich built on interactions with SPACA1 and FAM209, explaining the acrosome-detachment phenotype.

   Evidence Co-immunoprecipitation, Cylc1 knockout mouse, immunofluorescence, and whole exome sequencing of infertile men

   PMID:38573307

   Open questions at the time

   • Stoichiometry and structural arrangement of the sandwich complex not determined
   • Which other PT proteins participate not fully enumerated
3. 2024 Medium

   Showed that human CYLC1 missense variants act by mislocalizing the protein rather than reducing its expression, and that this perturbs acrosome morphology and PLCZ1 distribution, connecting variant biology to functional consequences.

   Evidence Western blotting, immunofluorescence, CRISPR/Cas9 Cylc1 KO mice, SEM/TEM, and Sanger sequencing of variant carriers

   PMID:41075067

   Open questions at the time

   • Single-lab study without independent replication
   • Mechanistic basis for variant-induced mislocalization not established
   • Causal link between PLCZ1 mislocalization and fertilization outcome not demonstrated

• Whether mammalian CYLC1 retains any microtubule-regulatory or tubulin-sequestering activity analogous to its C. elegans homologues remains unresolved.
• C. elegans cylc-1/cylc-2 microtubule-regulation function has not been tested in mammalian CYLC1
• No biochemical activity assigned to mammalian CYLC1 beyond its structural anchoring role