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Sorting nexin 27 regulates the lysosomal degradation of AQP2 protein in kidney collecting duct

We recently demonstrated that vacuolar protein sorting‐associated protein 35 (Vps35), a component of the retromer complex, interacts with the carboxyl terminus of aquaporin‐2, and depletion of Vps35 was associated with decreased AQP2 trafficking and increased lysosomal degradation of AQP2. Sorting nexin 27 (SNX27), a PDZ domain‐containing protein, is known to cooperate with the retromer complex in the recycling of early‐endosome to the plasma membrane. Since carboxyl terminus of aquaporin‐2 has the class I PDZ‐interacting motif (X‐Thr/Ser‐X‐Φ), we aimed to examine whether SNX27 could also play a role in the regulation of AQP2 trafficking and protein abundance in the kidney collecting duct cells. Immunohistochemistry revealed that SNX27 was diffusely labeled throughout the cytoplasm in the inner medullary collecting duct cells of rat kidney. Co‐immunoprecipitation assay of rat kidney inner medulla demonstrated that SNX27 interacted with AQP2. The role of SNX27 in the dDAVP‐responsive regulation of AQP2 trafficking and protein abundance was examined in mouse collecting duct mpkCCDc14 cells under siRNA‐mediated knockdown of SNX27. Cell surface biotinylation assay revealed that dDAVP‐induced translocation of AQP2 to the apical plasma membrane was decreased under SNX27 knockdown. Moreover, dDAVP‐induced AQP2 up‐regulation was significantly blunted in the cells with the siRNA‐mediated SNX27 knockdown. During the withdrawal period after dDAVP stimulation, the decrease of AQP2 protein abundance in the cells with SNX27 knockdown was attenuated by lysosomal inhibition with chloroquine co‐treatment. Taken together, SNX27 is an interacting protein with AQP2 and is likely to act as a component of the AQP2 sorting machinery after endocytosis, partly by regulating the lysosomal degradation of AQP2 protein abundance.