The Niemann-Pick C1 Protein Resides in a Vesicular Compartment Linked to Retrograde Transport of Multiple Lysosomal Cargo

Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder. A variety of studies have highlighted defective sterol trafficking from lysosomes in NP-C cells. However, the heterogeneous nature of additional accumulating metabolites suggests that the cellular lesion may involve a more...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-04, Vol.274 (14), p.9627-9635
Main Authors: Neufeld, E B, Wastney, M, Patel, S, Suresh, S, Cooney, A M, Dwyer, N K, Roff, C F, Ohno, K, Morris, J A, Carstea, E D, Incardona, J P, Strauss, 3rd, J F, Vanier, M T, Patterson, M C, Brady, R O, Pentchev, P G, Blanchette-Mackie, E J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibodies
Antigens, CD - metabolism
Biological Transport
Carrier Proteins
Cell Compartmentation
Cholesterol - metabolism
Endocytosis
Humans
Intracellular Signaling Peptides and Proteins
Lysosomal Membrane Proteins
Lysosomal-Associated Membrane Protein 2
Lysosomes - metabolism
Membrane Glycoproteins - metabolism
Molecular Sequence Data
Mutagenesis, Site-Directed
Niemann-Pick C1 Protein
Niemann-Pick Diseases - genetics
Niemann-Pick Diseases - metabolism
Proteins - genetics
Proteins - metabolism
Receptor, IGF Type 2 - metabolism
Structure-Activity Relationship
Sucrose - metabolism
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Summary:Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder. A variety of studies have highlighted defective sterol trafficking from lysosomes in NP-C cells. However, the heterogeneous nature of additional accumulating metabolites suggests that the cellular lesion may involve a more generalized block in retrograde lysosomal trafficking. Immunocytochemical studies in fibroblasts reveal that the NPC 1 gene product resides in a novel set of lysosome-associated membrane protein-2 (LAMP2)(+)/mannose 6-phosphate receptor(−) vesicles that can be distinguished from cholesterol-enriched LAMP2(+) lysosomes. Drugs that block sterol transport out of lysosomes also redistribute NPC1 to cholesterol-laden lysosomes. Sterol relocation from lysosomes in cultured human fibroblasts can be blocked at 21 °C, consistent with vesicle-mediated transfer. These findings suggest that NPC1(+) vesicles may transiently interact with lysosomes to facilitate sterol relocation. Independent of defective sterol trafficking, NP-C fibroblasts are also deficient in vesicle-mediated clearance of endocytosed [ 14 C]sucrose. Compartmental modeling of the observed [ 14 C]sucrose clearance data targets the trafficking defect caused by mutations in NPC1 to an endocytic compartment proximal to lysosomes. Low density lipoprotein uptake by normal cells retards retrograde transport of [ 14 C]sucrose through this same kinetic compartment, further suggesting that it may contain the sterol-sensing NPC1 protein. We conclude that a distinctive organelle containing NPC1 mediates retrograde lysosomal transport of endocytosed cargo that is not restricted to sterol.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.14.9627