Small Interactor of PKD2 (SIP), a novel PKD2-related single-pass transmembrane protein, is required for proteolytic processing and ciliary import of PKD2.

In cilia, the ciliopathy-relevant TRP channel PKD2 is spatially compartmentalized into a distal region, in which PKD2 binds the axoneme and extracellular mastigonemes, and a smaller proximal region, in which PKD2 is more mobile and lacks mastigonemes. Here, we show that the two PKD2 regions are established early during cilia regeneration and increase in length as cilia elongate. In abnormally long cilia, only the distal region elongated whereas both regions adjusted in length during cilia shortening. In dikaryon rescue experiments, tagged PKD2 rapidly entered the proximal region of PKD2-deficient cilia whereas assembly of the distal region was hindered, suggesting that axonemal docking of PKD2 requires ciliary assembly. We identified Small Interactor of PKD2 (SIP), a small PKD2-related protein, as a novel component of the PKD2-mastigoneme complex. In mutants, stability and proteolytic processing of PKD2 in the cell body were reduced and PKD2-mastigoneme complexes were absent from mutant cilia. Like the and mutants, swims with reduced velocity. Cilia of the mutant beat with normal frequency and bending pattern but were less efficient in moving cells supporting a passive role of the PKD2-SIP-mastigoneme complexes in increasing the effective surface of cilia.