title: The interactomics of sortilin: an ancient lysosomal receptor evolving new functions.
abstract: The delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6-phosphate receptor (MPR). The MPR has been demonstrated to attain the early endosomes via a process that requires the interaction of its cytosolic domain with the GGA and AP-1 adaptor proteins. Additionally, the MPR can be recycled back to the trans-Golgi network (TGN) through its interaction with the retromer complex. Interestingly, in I-cell disease (ICD), in which the MPR pathway is non-functional, many soluble lysosomal proteins continue to traffic to the lysosomes. This observation led to the discovery that sortilin is responsible for the MPR-independent targeting of the sphingolipid activator proteins (SAPs) and acid sphingomyelinase (ASM). More recently, our laboratory has tested the hypothesis that sortilin is also capable of sorting a variety of cathepsins that exhibit varying degrees of MPR-independent transport. We have demonstrated that the transport of cathepsin D is partially dependent upon sortilin, that cathepsin H requires sortilin, and that cathepsins K and L attain the lysosomes in a sortilin-independent fashion. As a type-1 receptor, sortilin also has numerous cytosolic binding partners. It has been observed that like the MPR, the anterograde trafficking of sortilin and its cargo require both GGAs and AP-1. Similarly, the retrograde recycling pathway of sortilin also involves an interaction with retromer through a YXXphi site in the cytosolic tail of sortilin. In conclusion, the cytosolic domains of sortilin and MPR possess a high degree of functional homology and both receptors share a conserved trafficking mechanism.
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec, Canada.
authors.forename: Maryssa
authors.initials: M
authors.lastname: Canuel
authors.forename: Yuan
authors.initials: Y
authors.lastname: Libin
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Morales
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D033961:Adaptor Protein Complex 1 / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D056655:Cathepsin H; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D009081:Mucolipidoses / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000502:physiology; D049128:Sphingolipid Activator Proteins / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism; D000099183:Sortilin
chemical_list: D020727:ADP-Ribosylation Factors; D033961:Adaptor Protein Complex 1; D033942:Adaptor Proteins, Vesicular Transport; D002402:Cathepsin D; D056655:Cathepsin H; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D006867:Hydrolases; D017527:Receptor, IGF Type 2; D049128:Sphingolipid Activator Proteins; D000099183:Sortilin; C407306:GGA adaptor proteins; C534281:CTSL protein, human; C534126:CTSH protein, human; C534130:CTSK protein, human