Synaptojanin 1-Mediated Pl(4,5)P2 Hydrolysis Is Modulated by Membrane Curvature and Facilitates Membrane Fission

Phosphatidylinositol-4,5-bisphosphate [Pl(4,5)P-2] plays a fundamental role in clathrin-mediated endocytosis. However, precisely how Pl(4,5)P-2 metabolism is spatially and temporally regulated during membrane internalization and the functional consequences of endocytosis-coupled Pl(4,5)P-2 dephosphorylation remain to be explored. Using cell-free assays with liposomes of varying diameters, we show that the major synaptic phosphoinositide phosphatase, synaptojanin 1 (Synj1), acts with membrane curvature generators/sensors, such as the BAR protein endophilin, to preferentially remove Pl(4,5)P-2 from curved membranes as opposed to relatively flat ones. Moreover, in vivo recruitment of Synj1's inositol 5-phosphatase domain to endophilin-induced membrane tubules results in fragmentation and condensation of these structures largely in a dynamin-dependent fashion. Our study raises the possibility that geometry-based mechanisms may contribute to spatially restricting Pl(4,5)P-2 elimination during membrane internalization and suggests that the Pl(4,5)P-2-to-Pl4P conversion achieved by Synj1 at sites of high curvature may cooperate with dynamin to achieve membrane fission.