PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function

Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3. P to control endocytic trafficking, but whether enzyme specialization occurs in defined subcellular locations is unclear. Here, we report that PI3K-C2α is enriched in the pericentriolar recycling endocytic compartment (PRE) at the base of the primary cilium, where it regulates production of a specific pool of PtdIns3. P. Loss of PI3K-C2α-derived PtdIns3. P leads to mislocalization of PRE markers such as TfR and Rab11, reduces Rab11 activation, and blocks accumulation of Rab8 at the primary cilium. These changes in turn cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) signaling and ultimately impair embryonic development. Selective reconstitution of PtdIns3. P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3. P pool at the PRE required for Rab11 and Shh pathway activation.