title: Sortilin turnover is mediated by ubiquitination.
abstract: Sortilin is a transmembrane domain protein that has been implicated in the sorting of prosaposin and other soluble cargo from the Golgi to the lysosomal compartment. While the majority of the receptor is recycled back to the Golgi from endosomes, it is known that upon successive rounds of transport, a proportion of sortilin is degraded in lysosomes. Recently, it was shown that sortilin is palmitoylated and that this post-translational modification prevents its degradation and enables sortilin to efficiently traffic back to the Golgi. Thus palmitoylation can be used to modulate the amount of receptor and hence cargo reaching the lysosome. In this work, we demonstrate that non-palmitoylated sortilin is ubiquitinated and internalized into the lysosomal compartment via the ESCRT pathway for degradation. Furthermore, we identified Nedd4 as an E3 ubiquitin ligase that mediates this post-translational modification. We propose a model where palmitoylation and ubiquitination play opposite roles in the stability and turnover of sortilin and serve as a control mechanism that balances the amount of lysosomal sorting and trafficking in cells.
authors.affiliation: Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC, Canada H1T 2M4.
authors.forename: Karine
authors.initials: K
authors.lastname: Dumaresq-Doiron
authors.forename: Felix
authors.initials: F
authors.lastname: Jules
authors.forename: Stephane
authors.initials: S
authors.lastname: Lefrancois
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation; D008239:Lysine / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D000075702:Nedd4 Ubiquitin Protein Ligases; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D056827:Endosomal Sorting Complexes Required for Transport; D008239:Lysine; D000075702:Nedd4 Ubiquitin Protein Ligases; D011994:Recombinant Proteins; D044767:Ubiquitin-Protein Ligases; D000099183:Sortilin; C000618483:Nedd4 protein, human