title: Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7.
abstract: The retromer complex mediates retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network (TGN). Mammalian retromer is composed of a sorting nexin (SNX) dimer that binds to phosphatidylinositol 3-phosphate-enriched endosomal membranes and a vacuolar protein sorting (Vps) 26/29/35 trimer that participates in cargo recognition. The mammalian SNX dimer is necessary but not sufficient for recruitment of the Vps26/29/35 trimer to membranes. In this study, we demonstrate that the guanosine triphosphatase Rab7 contributes to this recruitment. The Vps26/29/35 trimer specifically binds to Rab7-guanosine triphosphate (GTP) and localizes to Rab7-containing endosomal domains. Interference with Rab7 function causes dissociation of the Vps26/29/35 trimer but not the SNX dimer from membranes. This blocks retrieval of mannose 6-phosphate receptors to the TGN and impairs cathepsin D sorting. Rab5-GTP does not bind to the Vps26/29/35 trimer, but perturbation of Rab5 function causes dissociation of both the SNX and Vps26/29/35 components from membranes through inhibition of a pathway involving phosphatidylinositol 3-kinase. These findings demonstrate that Rab5 and Rab7 act in concert to regulate retromer recruitment to endosomes.
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rojas
authors.forename: Thijs
authors.initials: T
authors.lastname: van Vlijmen
authors.forename: Gonzalo A
authors.initials: GA
authors.lastname: Mardones
authors.forename: Yogikala
authors.initials: Y
authors.lastname: Prabhu
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Rojas
authors.forename: Shabaz
authors.initials: S
authors.lastname: Mohammed
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Peter
authors.initials: P
authors.lastname: van der Sluijs
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D019281:Dimerization; D011992:Endosomes / Q000502:physiology*; D005982:Glutathione Transferase / Q000502:physiology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006706:Homeostasis; D006867:Hydrolases / Q000378:metabolism; D008322:Mammals; D008565:Membrane Proteins / Q000502:physiology; D014617:Vacuoles / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D020696:rab5 GTP-Binding Proteins / Q000502:physiology*; D000090802:rab7 GTP-Binding Proteins; D021601:trans-Golgi Network / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D006160:Guanosine Triphosphate; D005982:Glutathione Transferase; D006867:Hydrolases; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins