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(American Journal of Pathology. 2005;166:499-510.)
© 2005 American Society for Investigative Pathology

The Wilson Disease Protein ATP7B Resides in the Late Endosomes with Rab7 and the Niemann-Pick C1 Protein

Masaru Harada^*, Takumi Kawaguchi^*, Hiroto Kumemura^*, Kunihiko Terada, Haruaki Ninomiya, Eitaro Taniguchi^*, Shinichiro Hanada^*, Shinji Baba^*, Michiko Maeyama^*, Hironori Koga^*, Takato Ueno^*, Koh Furuta, Tatsuo Suganuma^¶, Toshihiro Sugiyama and Michio Sata^*

From the Second Department of Medicine and Research Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science,^* Kurume University School of Medicine, Kurume; the Department of Biochemistry, Akita University School of Medicine, Akita; the Department of Neurobiology, Tottori University Faculty of Medicine, Yonago; the Department of Clinical Chemistry and Laboratory Medicine, National Cancer Center Hospital, Tokyo; and the Department of Anatomy, ^¶ Miyazaki Medical College, Miyazaki, Japan

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.

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