Loss of the human mucolipin-1 gene underlies mucolipidosis type IV (MLIV), a lysosomal storage disease that results in severe developmental neuropathology1-3. Unlike other lysosomal storage diseases, MLIV is not associated with a lack of lysosomal hydrolases4; instead, MLIV cells display abnormal endocytosis of lipids and accumulate large vesicles, indicating that a defect in endocytosis may underlie the disease4-6. Here we report the identification of a loss-of-function mutation in the Caenorhabditis elegans mucolipin-1 homolog, cup-5, and show that this mutation results in an enhanced rate of uptake of fluid-phase markers, decreased degradation of endocytosed protein and accumulation of large vacuoles. Overexpression of cup-S(+) causes the opposite phenotype, indicating that cup-5 activity controls aspects of endocytosis. Studies in model organisms such as C. elegans have helped illuminate fundamental mechanisms involved in normal cellular function and human disease; thus the C. elegans cup-5 mutant may be a useful model for studying conserved aspects of mucolipin-1 structure and function and for assessing the effects of potential therapeutic compounds.
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