title: The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types.
abstract: The misregulation of programmed cell death, or apoptosis, contributes to the pathogenesis of many diseases. We used Nomarski microscopy to screen for mutants containing refractile cell corpses in a C. elegans strain in which all programmed cell death is blocked and such corpses are absent. We isolated a mutant strain that accumulates refractile bodies resembling irregular cell corpses. We rescued this mutant phenotype with the C. elegans mucolipidosis type IV (ML-IV) homolog, the recently identified cup-5 (coelomocyte-uptake defective) gene. ML-IV is a human autosomal recessive lysosomal storage disease characterized by psychomotor retardation and ophthalmological abnormalities. Our null mutations in cup-5 cause maternal-effect lethality. In addition, cup-5 mutants contain excess lysosomes in many and possibly all cell types and contain lamellar structures similar to those observed in ML-IV cell lines. The human ML-IV gene is capable of rescuing both the maternal-effect lethality and the lysosome-accumulation abnormality of cup-5 mutants. cup-5 mutants seem to contain excess apoptotic cells as detected by staining with terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. We suggest that the increased apoptosis seen in cup-5 mutants is a secondary consequence of the lysosomal defect, and that abnormalities in apoptosis may be associated with human lysosomal storage disorders.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, 68-425, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Hersh
authors.forename: Erika
authors.initials: E
authors.lastname: Hartwieg
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020287:In Situ Nick-End Labeling; D008247:Lysosomes / Q000502:physiology*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation
chemical_list: C426649:CUP-5 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins