title: Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling.
abstract: Sealing of phagosomes is accompanied by the disappearance of phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P(2)) from their cytoplasmic leaflet. Elimination of PtdIns(4,5)P(2), which is required for actin remodeling during phagosome formation, has been attributed to hydrolysis by phospholipase C and phosphorylation by phosphatidylinositol 3-kinase. We found that two inositol 5-phosphatases, OCRL and Inpp5B, become associated with nascent phagosomes. Both phosphatases, which are Rab5 effectors, associate with the adaptor protein APPL1, which is recruited to the phagosomes by active Rab5. Knockdown of APPL1 or inhibition of Rab5 impairs association of OCRL and Inpp5B with phagosomes and prolongs the presence of PtdIns(4,5)P(2) and actin on their membranes. Even though APPL1 can serve as an anchor for Akt, its depletion accentuated the activation of the kinase, likely by increasing the amount of PtdIns(4,5)P(2) available to generate phosphatidylinositol (3,4,5)-trisphosphate. Thus, inositol 5-phosphatases are important contributors to the phosphoinositide remodeling and signaling that are pivotal for phagocytosis.
authors.affiliation: Division of Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Michal
authors.initials: M
authors.lastname: Bohdanowicz
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Balkin
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018613:Microscopy, Confocal; D010588:Phagosomes / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D049452:Green Fluorescent Proteins; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D020696:rab5 GTP-Binding Proteins; D000099182:Phosphoinositide 5-Phosphatases; C510733:Appl1 protein, mouse; C514862:Akt1 protein, mouse; C489581:Ocrl protein, mouse
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