title: Vps27 recruits ESCRT machinery to endosomes during MVB sorting.
abstract: Down-regulation (degradation) of cell surface proteins within the lysosomal lumen depends on the function of the multivesicular body (MVB) sorting pathway. The function of this pathway requires the class E vacuolar protein sorting (Vps) proteins. Of the class E Vps proteins, both the ESCRT-I complex (composed of the class E proteins Vps23, 28, and 37) and Vps27 (mammalian hepatocyte receptor tyrosine kinase substrate, Hrs) have been shown to interact with ubiquitin, a signal for entry into the MVB pathway. We demonstrate that activation of the MVB sorting reaction is dictated largely through interactions between Vps27 and the endosomally enriched lipid species phosphatidylinositol 3-phosphate via the FYVE domain (Fab1, YGL023, Vps27, and EEA1) of Vps27. ESCRT-I then physically binds to Vps27 on endosomal membranes via a domain within the COOH terminus of Vps27. A peptide sequence in this domain, PTVP, is involved in the function of Vps27 in the MVB pathway, the efficient endosomal recruitment of ESCRT-I, and is related to a motif in HIV-1 Gag protein that is capable of interacting with Tsg101, the mammalian homologue of Vps23. We propose that compartmental specificity for the MVB sorting reaction is the result of interactions of Vps27 with phosphatidylinositol 3-phosphate and ubiquitin. Vps27 subsequently recruits/activates ESCRT-I on endosomes, thereby facilitating sorting of ubiquitinated MVB cargoes.
authors.affiliation: Department of Cellular and Molecular Medicine, and Howard Hughes Medical Institute, University of California, San Diego School of Medicine, La Jolla, CA 92093-0688, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Katzmann
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Stefan
authors.forename: Markus
authors.initials: M
authors.lastname: Babst
authors.forename: Scott D
authors.initials: SD
authors.lastname: Emr
mesh_terms: D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D046911:Macromolecular Substances; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D046911:Macromolecular Substances; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D033921:Vesicular Transport Proteins; C115245:SRN2 protein, S cerevisiae; C425333:STP22 protein, S cerevisiae; C119627:VPS27 protein, S cerevisiae; C102954:VPS28 protein, S cerevisiae; C055525:phosphatidylinositol 3-phosphate