Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content
| Autor: | Allyn Michael Kaufmann, Jeffrey P. Krise |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Biogenic Amines
Endosome Endosomes Biology Membrane Fusion Biochemistry Niemann-Pick C1 Protein hemic and lymphatic diseases Lysosome medicine Humans Molecular Biology Cells Cultured Late endosome Niemann-Pick Diseases Aldehydes Oxidoreductases Acting on CH-NH Group Donors Membrane Glycoproteins Mannose 6-phosphate receptor Propylamines Organelle lumen Intracellular Signaling Peptides and Proteins nutritional and metabolic diseases Biological Transport Cell Biology Fibroblasts medicine.disease Cell biology Membrane Transport Structure Function and Biogenesis medicine.anatomical_structure NPC1 Carrier Proteins Lysosomes Niemann–Pick disease Polyamine oxidase |
| Zdroj: | Journal of Biological Chemistry. 283:24584-24593 |
| ISSN: | 0021-9258 |
| Popis: | Mutations in the late endosomal/lysosomal membrane protein Niemann-Pick C1 (NPC1) are known to cause a generalized block in retrograde vesicle-mediated transport, resulting in the hyper-accumulation of multiple lysosomal cargos. An important, yet often overlooked, category of lysosomal cargo includes the vast array of small molecular weight amine-containing molecules that are substrates for ion trapping in the highly acidic organelle lumen. We show here that the introduction of amine-containing molecules in lysosomes can significantly stimulate NPC1-mediated late endosome/lysosome fusion, and subsequently the secretion of lysosomal cargo. To illustrate the physiological importance of this NPC1-mediated transport pathway, we show that NPC1-deficient cells are more susceptible to the toxic effects of a lysosomotropic polyamine metabolite 3-aminopropanal. Moreover, NPC fibroblasts are shown to have higher levels of polyamine oxidase, an enzyme involved in the formation of 3-aminopropanal. Collectively, these findings provide strong support for a novel functional role for NPC1 and may also provide clues toward understanding NPC disease progression. |
| Databáze: | OpenAIRE |
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