title: Synaptojanin 1-mediated PI(4,5)P2 hydrolysis is modulated by membrane curvature and facilitates membrane fission.
abstract: Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P₂] plays a fundamental role in clathrin-mediated endocytosis. However, precisely how PI(4,5)P₂ metabolism is spatially and temporally regulated during membrane internalization and the functional consequences of endocytosis-coupled PI(4,5)P₂ 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 PI(4,5)P₂ 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 PI(4,5)P₂ elimination during membrane internalization and suggests that the PI(4,5)P₂-to-PI4P conversion achieved by Synj1 at sites of high curvature may cooperate with dynamin to achieve membrane fission.
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Belle
authors.initials: B
authors.lastname: Chang-Ileto
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Frere
authors.forename: Robin B
authors.initials: RB
authors.lastname: Chan
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Voronov
authors.forename: Aurélien
authors.initials: A
authors.lastname: Roux
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D034281:Dynamins / Q000378:metabolism; D006868:Hydrolysis; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008081:Liposomes; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C498434:Sh3gl2 protein, mouse; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases; D034281:Dynamins