Mutations in PKD2, which encodes the calcium-activated calcium channel polycystin-2 (PC2), underlie around 15% of the cases of autosomal dominant polycystic kidney disease (ADPKD). PC2 is mainly localised to the ER, but also functions in the primary cilia of renal tubule epithelia in a complex with PC1. Mutants of either protein that are defective in ciliary trafficking are known to be pathogenic; however, it is unclear how polycystins are transported through the endosomal system. A previous proteomics screen by Pete Cullen and colleagues found PC2 as a putative interaction partner of retromer, a heterotrimeric complex at the endosome membrane that promotes the retrieval of transmembrane protein from a degradative route. In their present work (Tilley et al., 2018), the authors now validate and further study this interaction in kidney tubule cells. They show that PC2 associates with retromer through a cytoplasmic N-terminal motif, G-x-x-I-E-M-Q-x-I-x, which bears no similarity to other retromer-interacting sequences. However, PC2 is not able to interact with the different retromer subunits in isolation, suggesting that its binding involves multivalent interactions. Importantly, their data suggest that retromer associates preferentially with the trafficking population of PC2 that has exited the ER, indicating PC2 might indeed be a retromer cargo. This also raises interesting questions with regard to the functional consequence of an interaction between an ER-resident calcium channel and the endosomal sorting machinery.
