title: A shortcut to the lysosome: the mannose-6-phosphate-independent pathway.
abstract: Lysosomal hydrolases have long been known to be responsible for the degradation of different substrates in the cell. These acid hydrolases are synthesized in the rough endoplasmic reticulum and transported through the Golgi apparatus to the trans-Golgi network (TGN). From there, they are delivered to endosomal/lysosomal compartments, where they finally become active due to the acidic pH characteristic of the lysosomal compartment. The majority of the enzymes leave the TGN after modification with mannose-6-phosphate (M6P) residues, which are specifically recognized by M6P receptors (MPRs), ensuring their transport to the endosomal/lysosomal system. Although M6P receptors play a major role in the intracellular transport of newly synthesized lysosomal enzymes in mammalian cells, several lines of evidence suggest the existence of alternative processes of lysosomal targeting. Among them, the two that are mediated by the M6P alternative receptors, lysosomal integral membrane protein (LIMP-2) and sortilin, have gained unequivocal support. LIMP-2 was shown to be implicated in the delivery of beta-glucocerebrosidase (GCase) to the lysosomes, whereas sortilin has been suggested to be a multifunctional receptor capable of binding several different ligands, including neurotensin and receptor-associated protein (RAP), and of targeting several proteins to the lysosome, including sphingolipid activator proteins (prosaposin and GM2 activator protein), acid sphingomyelinase and cathepsins D and H. Here, we review the current knowledge on these two proteins: their discovery, study, structural features and cellular function, with special attention to their role as alternative receptors to lysosomal trafficking. Recent studies associating both LIMP2 and sortilin to disease are also extensively reviewed.
authors.affiliation: Research and Development Unit, Department of Genetics, CGMJM, INSA, Portugal. francisca_coutinho@yahoo.com
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: Coutinho
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Prata
authors.forename: Sandra
authors.initials: S
authors.lastname: Alves
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D049289:G(M2) Activator Protein / Q000378:metabolism; D005962:Glucosylceramidase / Q000378:metabolism; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008360:Mannosephosphates / Q000378:metabolism; D009496:Neurotensin / Q000378:metabolism; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D051116:Receptors, Scavenger / Q000172:deficiency* / Q000235:genetics; D049231:Saposins / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D002403:Cathepsins; D049289:G(M2) Activator Protein; D005962:Glucosylceramidase; D051907:Lysosomal Membrane Proteins; D008360:Mannosephosphates; D009496:Neurotensin; D017527:Receptor, IGF Type 2; D051116:Receptors, Scavenger; D049231:Saposins; D013108:Sphingomyelin Phosphodiesterase; D000099183:Sortilin; C483345:PSAP protein, human; C074299:SCARB2 protein, human; C027693:mannose-6-phosphate