C2cd6-encoded CatSperτ targets sperm calcium channel to Ca²⁺ signaling domains in the flagellar membrane

In mammalian sperm cells, regulation of spatiotemporal Ca²⁺ signaling relies on the quadrilinear Ca²⁺ signaling nanodomains in the flagellar membrane. The sperm-specific, multi-subunit CatSper Ca²⁺ channel, which is crucial for sperm hyperactivated motility and male fertility, organizes the nanodomains. Here, we report CatSperτ, the C2cd6-encoded membrane-associating C2 domain protein, can independently migrate to the flagella and serve as a major targeting component of the CatSper channel complex. CatSperτ loss of function in mice demonstrates that it is essential for sperm hyperactivated motility and male fertility. CatSperτ targets the CatSper channel into the quadrilinear nanodomains in the flagella of developing spermatids, whereas it is dispensable for functional channel assembly. CatSperτ interacts with ciliary trafficking machinery in a C2-dependent manner. These findings provide insights into the CatSper channel trafficking to the Ca²⁺ signaling nanodomains and the shared molecular mechanisms of ciliary and flagellar membrane targeting.