Niemann-Pick C1 protein transports copper to the secretory compartment from late endosomes where ATP7B resides

Wilson disease is a genetic disorder characterized by the accumulation of copper in the body by defective biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. However, copper metabolism in hepatocytes has...

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Bibliographic Details
Published in:Experimental cell research 2009-01, Vol.315 (2), p.119-126
Main Authors: Yanagimoto, Chikatoshi, Harada, Masaru, Kumemura, Hiroto, Koga, Hironori, Kawaguchi, Takumi, Terada, Kunihiko, Hanada, Shinichiro, Taniguchi, Eitaro, Koizumi, Yukio, Koyota, Souichi, Ninomiya, Haruaki, Ueno, Takato, Sugiyama, Toshihiro, Sata, Michio
Format: Article
Language:English
Subjects:
Adaptor Protein Complex gamma Subunits - metabolism
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - metabolism
Androstenes - pharmacology
Anticholesteremic Agents - pharmacology
ATP7B
Biological Transport - drug effects
Biological Transport - physiology
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Carrier Proteins - genetics
Carrier Proteins - physiology
Cation Transport Proteins - genetics
Cation Transport Proteins - metabolism
Cell Line, Tumor
Cellular biology
Ceruloplasmin
Ceruloplasmin - metabolism
Copper
Copper - metabolism
Copper-Transporting ATPases
Endosomes - metabolism
Genetic disorders
Humans
Intracellular Signaling Peptides and Proteins
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Lysosomal Membrane Proteins - metabolism
Lysosomal-Associated Membrane Protein 2
Medical research
Membrane Glycoproteins - genetics
Membrane Glycoproteins - physiology
Mutation
Niemann-Pick C1 Protein
Niemann-Pick disease type C
NPC1
Proteins
rab GTP-Binding Proteins - metabolism
Rab7
rab7 GTP-Binding Proteins
RNA Interference
RNA, Small Interfering - genetics
Wilson disease
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Summary:Wilson disease is a genetic disorder characterized by the accumulation of copper in the body by defective biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. However, copper metabolism in hepatocytes has been still unclear. Niemann-Pick disease type C (NPC) is a lipid storage disorder and the most commonly mutated gene is NPC1 and its gene product NPC1 is a late endosome protein and regulates intracellular vesicle traffic. In the present study, we induced NPC phenotype and examined the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp. The vesicle traffic was modulated using U18666A, which induces NPC phenotype, and knock down of NPC1 by RNA interference. ATP7B colocalized with the late endosome markers, but not with the trans-Golgi network markers. U18666A and NPC1 knock down decreased holo-Cp secretion to culture medium, but did not affect the secretion of other secretory proteins. Copper accumulated in the cells after the treatment with U18666A. These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via NPC1-dependent pathway and incorporated into apo-Cp to form holo-Cp.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2008.10.022