OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates.
Mutation of the inositol 5-phosphatase OCRL1 causes Lowe syndrome and Dent-2 disease. Loss of OCRL1 function perturbs several cellular processes, including membrane traffic, but the underlying mechanisms remain poorly defined. Here we show that OCRL1 is part of the membrane-trafficking machinery operating at the trans-Golgi network (TGN)/endosome interface. OCRL1 interacts via IPIP27A with the F-BAR protein pacsin 2. OCRL1 and IPIP27A localize to mannose 6-phosphate receptor (MPR)-containing trafficking intermediates, and loss of either protein leads to defective MPR carrier biogenesis at the TGN and endosomes. OCRL1 5-phosphatase activity, which is membrane curvature sensitive, is stimulated by IPIP27A-mediated engagement of OCRL1 with pacsin 2 and promotes scission of MPR-containing carriers. Our data indicate a role for OCRL1, via IPIP27A, in regulating the formation of pacsin 2-dependent trafficking intermediates and reveal a mechanism for coupling PtdIns(4,5)P2 hydrolysis with carrier biogenesis on endomembranes.
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Peter G
PG
Billcliff
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Christopher J
CJ
Noakes
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Zenobia B
ZB
Mehta
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Guanhua
G
Yan
Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom.
LokHang
L
Mak
Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom.
Rudiger
R
Woscholski
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom martin.lowe@manchester.ac.uk.
Martin
M
Lowe
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D053040:Nephrolithiasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009800:Oculocerebrorenal Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010716:Phosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; C120714:PACSIN2 protein, human; D010716:Phosphatidylinositols; D017527:Receptor, IGF Type 2; C471696:SCRN1 protein, human; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human; D000072181:Inositol Polyphosphate 5-Phosphatases