Abstract
We have identified the aspartic protease cathepsin D as a novel intracellular target protein for the lipid second messenger ceramide. Ceramide specifically binds to and induces CTSD proteolytic activity. A-SMase deficient cells derived from Niemann-Pick patients show decreased CTSD activity that was reconstituted by transfection with A-SMase cDNA. Ceramide accumulation in cells derived from A-ceramidase defective Farber patients correlates with enhanced CTSD activity. These findings suggest that A-SMase-derived ceramide targets endolysosomal CTSD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / deficiency
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Amidohydrolases / genetics
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Animals
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Apoptosis
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Cathepsin D / deficiency
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Cathepsin D / genetics
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Cathepsin D / metabolism*
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Cell Compartmentation
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Cell Line, Transformed
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Ceramidases
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Ceramides / pharmacology
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Ceramides / physiology*
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Cytokines / physiology
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DNA, Complementary / genetics
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Enzyme Activation / drug effects
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Fibroblasts / enzymology
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Fibroblasts / pathology
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HeLa Cells / metabolism
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Humans
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Lipid Metabolism
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Lymphocytes / enzymology
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Lysosomes / enzymology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Niemann-Pick Diseases / enzymology
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Niemann-Pick Diseases / genetics
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Niemann-Pick Diseases / pathology
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Recombinant Fusion Proteins / metabolism
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Second Messenger Systems / physiology*
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Sphingomyelin Phosphodiesterase / deficiency
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Sphingomyelin Phosphodiesterase / genetics
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Sphingomyelin Phosphodiesterase / physiology*
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Tumor Cells, Cultured
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U937 Cells / metabolism
Substances
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Ceramides
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Cytokines
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DNA, Complementary
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Isoenzymes
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Recombinant Fusion Proteins
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Sphingomyelin Phosphodiesterase
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Cathepsin D
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Amidohydrolases
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Ceramidases