Retromer is involved in epithelial sodium channel trafficking.

The epithelial sodium channel, ENaC, located at the apical membrane in many epithelia, is the rate-limiting step for sodium reabsorption. Tight regulation of the plasma membrane population of ENaC is required as hyper- or hypotension may result if too many or too few ENaCs are present. Endocytosed ENaC travels to the early endosome and is then either trafficked to the lysosome for degradation or recycled back to the plasma membrane. Recently, the retromer recycling complex, located at the early endosome, has been implicated in plasma membrane protein recycling pathways. We hypothesized that retromer is required for recycling of ENaC. Stabilization of retromer function with the retromer stabilizing chaperone R55 increased ENaC current, while knockdown or overexpression of individual retromer and associated proteins altered ENaC current and cell surface population of ENaC. KIBRA was identified as an ENaC binding protein allowing ENaC to link to Snx4 to alter ENaC trafficking. Knockdown of the retromer-associated cargo-binding Snx27 protein did not alter ENaC current, whereas CCDC22, a CCC-complex protein, coimmunoprecipitated with ENaC and CCDC22 knockdown decreased ENaC current and population at the cell surface. Together our results confirm that retromer and the CCC complex play a role in recycling of ENaC to the plasma membrane.