C2cd6-encoded CatSper{tau} 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 CatSper{tau}, 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. CatSper{tau} loss-of-function in mice demonstrates that it is essential for sperm hyperactivated motility and male fertility. CatSper{tau} targets the CatSper channel into the quadrilinear nanodomains in the flagella of developing spermatids, whereas it is dispensable for functional channel assembly. CatSper{tau} 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. HighlightsO_LICatSper{tau} encoded by C2cd6 is a C2 membrane-associating domain containing protein C_LIO_LICatSper{tau} loss-of-function impairs sperm hyperactivation and male fertility C_LIO_LICatSper{tau} adopts ciliary trafficking machineries for flagellar targeting via C2 domain C_LIO_LICatSper{tau} targets the CatSper channel into nanodomains of developing sperm flagella C_LI