title: Lysosomal membrane protein composition, acidic pH and sterol content are regulated via a light-dependent pathway in metazoan cells.
abstract: In metazoans, lysosomes are characterized by a unique tubular morphology, acidic pH, and specific membrane protein (LAMP) and lipid (cholesterol) composition as well as a soluble protein (hydrolases) composition. Here we show that perturbation to the eye-color gene, light, results in impaired lysosomal acidification, sterol accumulation, altered endosomal morphology as well as compromised lysosomal degradation. We find that Drosophila homologue of Vps41, Light, regulates the fusion of a specific subset of biosynthetic carriers containing characteristic endolysosomal membrane proteins, LAMP1, V0-ATPase and the cholesterol transport protein, NPC1, with the endolysosomal system, and is then required for the morphological progression of the multivesicular endosome. Inhibition of Light results in accumulation of biosynthetic transport intermediates that contain these membrane cargoes, whereas under similar conditions, endosomal delivery of soluble hydrolases, previously shown to be mediated by Dor, the Drosophila homologue of Vps18, is not affected. Unlike Dor, Light is recruited to endosomes in a PI3P-sensitive fashion wherein it facilitates fusion of these biosynthetic cargoes with the endosomes. Depletion of the mammalian counterpart of Light, hVps41, in a human cell line also inhibits delivery of hLAMP to endosomes, suggesting an evolutionarily conserved pathway in metazoa.
authors.affiliation: National Centre for Biological Sciences, Bangalore, India.
authors.forename: M G
authors.initials: MG
authors.lastname: Swetha
authors.forename: V
authors.initials: V
authors.lastname: Sriram
authors.forename: K S
authors.initials: KS
authors.lastname: Krishnan
authors.forename: Viola M J
authors.initials: VM
authors.lastname: Oorschot
authors.forename: Corlinda
authors.initials: C
authors.lastname: ten Brink
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
authors.forename: Satyajit
authors.initials: S
authors.lastname: Mayor
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006867:Hydrolases / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins; D000077296:Niemann-Pick C1 Protein; D021381:Protein Transport / Q000235:genetics; D017494:Proton Pumps / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C104790:DOR protein, Drosophila; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D000077296:Niemann-Pick C1 Protein; C506965:Npc1a protein, Drosophila; D017494:Proton Pumps; D013261:Sterols; C549959:VPS41 protein, human; D033921:Vesicular Transport Proteins; D002784:Cholesterol; D006867:Hydrolases; D000251:Adenosine Triphosphatases; D025262:Vacuolar Proton-Translocating ATPases; C550849:Vha100-1 protein, Drosophila; C539468:Vps4 protein, Drosophila