title: Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer.
abstract: fEndosome-to-Golgi retrieval of the mannose 6-phosphate receptor (MPR) is required for lysosome biogenesis. Currently, this pathway is poorly understood. Analyses in yeast identified a complex of proteins called "retromer" that is essential for endosome-to-Golgi retrieval of the carboxypeptidase Y receptor Vps10p. Retromer comprises five distinct proteins: Vps35p, 29p, 26p, 17p, and 5p, which are conserved in mammals. Here, we show that retromer is required for the efficient retrieval of the cation-independent MPR (CI-MPR). Cells lacking mammalian VPS26 fail to retrieve the CI-MPR, resulting in either rapid degradation of or mislocalization to the plasma membrane. We have localized mVPS26 to multivesicular body endosomes by electron microscopy, and through the use of CD8 reporter protein constructs have examined the effect of loss of mVPS26 upon the trafficking of membrane proteins that cycle between the endosome and the Golgi. The data presented here support the hypothesis that retromer performs a selective function in endosome-to-Golgi transport, mediating retrieval of the CI-MPR, but not furin.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY, England, UK. mnjs100@cam.ac.uk
authors.forename: Matthew N J
authors.initials: MN
authors.lastname: Seaman
mesh_terms: D016564:Amyloid beta-Protein Precursor; D000818:Animals; D016827:CD8 Antigens / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D045683:Furin / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D058255:Protease Nexins; D021381:Protein Transport / Q000502:physiology; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D011956:Receptors, Cell Surface; D022161:Transport Vesicles / Q000378:metabolism / Q000648:ultrastructure; D033921:Vesicular Transport Proteins
chemical_list: D016564:Amyloid beta-Protein Precursor; D016827:CD8 Antigens; D002352:Carrier Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D058255:Protease Nexins; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; C498296:VPS26A protein, human; D033921:Vesicular Transport Proteins; C089989:Vps26 protein, mouse; D045683:Furin