PI3K-C2α regulates Polycystin-2 ciliary entry to prevent kidney cyst formation

Results PI3K-C2a resides at the recycling endosome compartment surrounding the primary cilium base where it controls the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. Consistently, partial reduction of PI3K-C2a is sufficient to impair elongation of the cilium both in Pik3c2a-silenced IMCD3 cells and in kidney tubules of Pik3c2a mice. Importantly, absence of PI3K-C2a impairs the Rab8-dependent transport of Polycystin-2 to cilia and produces an overactivation of proliferative pathways regulated by ciliary Polycystins, such as the mTOR and MAPK pathways. Both defects can be rescued by transfection of constitutively active Rab8. In line with defective Polycystin signaling, heterozygous deletion of PI3K-C2a in mice causes an overall deregulation of proliferative signals in response to Ischemia/Reperfusioninduced renal damage, and this condition predisposes to cyst development.