Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C. elegans

Development. 2006 Oct;133(19):3939-48. doi: 10.1242/dev.02575. Epub 2006 Aug 30.

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