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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP-Binding Cassette Transporters / genetics*
-
Animals
-
Apoptosis / genetics
-
Biological Transport
-
Caenorhabditis elegans / genetics
-
Caenorhabditis elegans / metabolism*
-
Caenorhabditis elegans Proteins / analysis
-
Caenorhabditis elegans Proteins / genetics*
-
Caenorhabditis elegans Proteins / metabolism*
-
Cathepsin L
-
Cathepsins / metabolism
-
Cysteine Endopeptidases / metabolism
-
Embryo, Nonmammalian / metabolism
-
Embryo, Nonmammalian / ultrastructure
-
Endocytosis / genetics
-
Genes, Lethal*
-
Intestinal Mucosa / metabolism
-
Intestines / embryology
-
Intestines / ultrastructure
-
Lysosomes / chemistry
-
Lysosomes / metabolism*
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mucolipidoses / genetics*
-
Multidrug Resistance-Associated Proteins / analysis
-
Multidrug Resistance-Associated Proteins / genetics*
-
Multidrug Resistance-Associated Proteins / metabolism*
-
Mutation
-
Suppression, Genetic
-
Vacuoles / chemistry
-
Vacuoles / metabolism
Substances
-
ATP-Binding Cassette Transporters
-
CUP-5 protein, C elegans
-
Caenorhabditis elegans Proteins
-
MRP-4 protein, C elegans
-
Membrane Proteins
-
Multidrug Resistance-Associated Proteins
-
Cathepsins
-
Cysteine Endopeptidases
-
CTSL protein, human
-
Cathepsin L