The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein.
Wilson disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion. Although the Wilson disease gene has been cloned, the cellular localization of the gene product (ATP7B) has not been fully clarified. Therefore, the precise physiological action of ATP7B is still unknown. We examined the distribution of ATP7B using an anti-ATP7B antibody, green fluorescent protein (GFP)-ATP7B (GFP-ATP7B) and ATP7B-DsRed in various cultured cells. Intracellular organelles were visualized by fluorescence microscopy. The distribution of ATP7B was compared with that of Rab7 and Niemann-Pick C1 (NPC1), proteins that localize in the late endosomes. U18666A, which induces the NPC phenotype, was used to modulate the intracellular vesicle traffic. GFP-ATP7B colocalized with various late endosome markers including Rab7 and NPC1 but not with Golgi or lysosome markers. U18666A induced the formation of late endosome-lysosome hybrid organelles, with GFP-ATP7B localized with NPC1 in these structures. We have confirmed that ATP7B is a late endosome-associated membrane protein. ATP7B appears to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes. Thus, defective copper ATPase activity of ATP7B in the late endosomes appears to be the main defect of Wilson disease.
Harada
Masaru
M
Second Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume 830-0011, Japan. harada@med.kurume-u.ac.jp
Kawaguchi
Takumi
T
Kumemura
Hiroto
H
Terada
Kunihiko
K
Ninomiya
Haruaki
H
Taniguchi
Eitaro
E
Hanada
Shinichiro
S
Baba
Shinji
S
Maeyama
Michiko
M
Koga
Hironori
H
Ueno
Takato
T
Furuta
Koh
K
Suganuma
Tatsuo
T
Sugiyama
Toshihiro
T
Sata
Michio
M
D000251:Adenosine Triphosphatases / Q000096:biosynthesis*; D001652:Bile Ducts / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis*; D027682:Cation Transport Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D019327:Copper Sulfate / Q000494:pharmacology; D000073840:Copper-Transporting ATPases; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D010641:Phenotype; D021381:Protein Transport; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis*; D000090802:rab7 GTP-Binding Proteins
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002614:Chelating Agents; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D003300:Copper; D000251:Adenosine Triphosphatases; D020691:rab GTP-Binding Proteins; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D019327:Copper Sulfate