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Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog

Nature Genetics volume 28, pages 64–68 (2001)Cite this article

Abstract

Loss of the human mucolipin-1 gene underlies mucolipidosis type IV (MLIV), a lysosomal storage disease that results in severe developmental neuropathology1,2,3. 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 disease4,5,6. 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-5(+) 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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Figure 1: Nomarski and epifluorescence images of the arIs37[pmyo-3::ssGFP] (a–c) and cup-5(ar465); arIs37[pmyo-3::ssGFP] (d–f) worms.
Figure 2: CUP-5 sequence and multiple sequence alignment.
Figure 3: CUP-5 overexpression.
Figure 4: CUP-5 localization in neurons.
Figure 5: BSA–Texas red injections into the pseudocoelom of arIs37[pmyo-3::ssGFP], cup-5(ar465); arIs37[pmyo-3::ssGFP], rme-8::GFP and cup-5(ar465); rme-8::GFP worms.
Figure 6: Heat-shock expression of secreted GFP.

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Acknowledgements

We thank D. Hirsh for inspiring our interest in coelomocytes; B. Grant and Y. Zhang for reagents and discussions; P. Loria and O. Hobert for the coelomocyte-specific promoter; A. Coulson and Y. Kohara for cosmid and cDNA clones; R. Ruiz and I. Temkin for technical assistance; B. Grant, S. Jarriault, D. Shaye and Y. Zhang for critical reading of the manuscript; and past and present members of the Greenwald, Hirsh and Hobert laboratories for discussions. I.G. is an Investigator of the Howard Hughes Medical Institute. H.F. was supported by an award from the Metropolitan Life Foundation to I.G.

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  1. Hanna Fares

    Present address: Department of Molecular and Cellular Biology, The University of Arizona, Life Sciences South Room 531, Tucson, Arizona, USA

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  1. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Hanna Fares & Iva Greenwald

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Fares, H., Greenwald, I. Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet 28, 64–68 (2001). https://doi.org/10.1038/ng0501-64

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