Phosphatidylinositol control of endocytosis

During clathrin-mediated endocytosis (CME), the phosphoinositide phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P₂) recruits proteins involved in the formation of clathrin-coated pits (CCPs). During subsequent endosomal stages, PtdIns(3)P predominates. Investigating how such phosphatidylinositol switching is achieved, Haucke and colleagues (Nature 499, 233–237; 2013) have identified a previously uncharacterized function for PtdIns(3,4)P₂ in CME. They showed that depleting this lipid or the class II PtdIns(3) kinase C2α (PI(3)K C2α, which phosphorylates PtdIns(4)P) from CCPs, inhibited transferrin CME and led to increased transferrin receptor surface levels. Furthermore, CCPs were longer-lived, and quantitative morphometric analysis revealed that PI(3)K C2α was required for the transition from invaginated to omega-shaped CCPs during maturation, before dynamin-mediated fission. The delay in CCP maturation caused by depleting PI(3)K C2α or PI(3,4)P₂ prompted a search for PtdIns(3,4)P₂ effectors at CCPs, which revealed that the PX-BAR domain protein sorting nexin 9 (SNX9) bound preferentially to PtdIns(3,4)P₂ over PtdIns(4,5)P₂ in brain extracts, and failed to accumulate at late-stage endocytic intermediates when PtdIns(3,4)P₂ or PI(3)K C2α was depleted from cells. These results have uncovered that PtdIns(3,4)P₂ functions in CME through the action of PI(3)K C2α and possibly in conjunction with PtdIns(4,5)P₂ phosphatases, adding to our understanding of how endocytosis is spatiotemporally controlled, and providing impetus to study this lipid in other aspects of physiology and disease.