title: Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C. elegans.
abstract: Mutations in MCOLN1, which encodes the protein mucolipin 1, result in the lysosomal storage disease mucolipidosis Type IV. Studies on human mucolipin 1 and on CUP-5, the Caenorhabditis elegans ortholog of mucolipin 1, have shown that these proteins are required for lysosome biogenesis/function. Loss of CUP-5 results in a defect in lysosomal degradation, leading to embryonic lethality. We have identified a mutation in the ABC transporter MRP-4 that rescues the degradation defect and the corresponding lethality, owing to the absence of CUP-5. MRP-4 localizes to endocytic compartments and its levels are elevated in the absence of CUP-5. These results indicate that the lysosomal degradation defect is exacerbated in some cells because of the accumulation of MRP-4 in lysosomes rather than the loss of CUP-5 per se. We also show that under some conditions, loss of MRP-4 rescues the embryonic lethality caused by the loss of the cathepsin L protease, indicating that the accumulation of ABC transporters may be a more general mechanism whereby an initial lysosomal dysfunction is more severely compromised.
authors.affiliation: Department of Molecular and Cellular Biology, Life Sciences South Room 531, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Schaheen
authors.forename: Greg
authors.initials: G
authors.lastname: Patton
authors.forename: Hanna
authors.initials: H
authors.lastname: Fares
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001692:Biological Transport; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000648:ultrastructure; D004705:Endocytosis / Q000235:genetics; D005804:Genes, Lethal; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology / Q000648:ultrastructure; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009081:Mucolipidoses / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D013489:Suppression, Genetic; D014617:Vacuoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D029742:Caenorhabditis elegans Proteins; D056668:Cathepsin L; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C426649:CUP-5 protein, C elegans; C515013:MRP-4 protein, C elegans; C534281:CTSL protein, human