Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C. elegans.
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.
Schaheen
Lara
L
Department of Molecular and Cellular Biology, Life Sciences South Room 531, University of Arizona, Tucson, AZ 85721, USA.
Patton
Greg
G
Fares
Hanna
H
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
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