Copper-induced translocation of the Wilson disease protein ATP7B independent of Murr1/COMMD1 and Rab7.
Wilson disease is a genetic disorder of copper metabolism. Impaired biliary excretion results in a gradual accumulation of copper, which leads to severe disease. The specific gene defect lies in the Wilson disease protein, ATP7B, a copper-transporting ATPase that is highly active in hepatocytes. The two major functions of ATP7B in the liver are the copper loading of ceruloplasmin in the Golgi apparatus, and the excretion of excess copper into the bile. In response to elevated copper levels, ATP7B shows a unique intracellular trafficking pattern that is required for copper excretion from the Golgi apparatus into dispersed vesicles. We analyzed the translocation of ATP7B by both confocal microscopy and RNA interference, testing current models that suggest the involvement of Murr1/COMMD1 and Rab7 in this pathway. We found that although the ATP7B translocation is conserved among nonhepatic cell lines, there is no co-localization with Murr1/COMMD1 or the Rab marker proteins of the endolysosomal system. Consistent with this finding, the translocation of ATP7B was not impaired by the depletion of either Murr1/COMMD1 or Rab7, or by a dominant-negative Rab7 mutant. In conclusion, our data suggest that the translocation of ATP7B takes place independently of Rab7-regulated endosomal traffic events. Murr1/COMMD1 plays a role in a later step of the copper excretion pathway but is not involved in the translocation of the Wilson disease protein.
Weiss
Karl Heinz
KH
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Lozoya
Javier Carbajo
JC
Tuma
Sabine
S
Gotthardt
Daniel
D
Reichert
Jürgen
J
Ehehalt
Robert
R
Stremmel
Wolfgang
W
Füllekrug
Joachim
J
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; 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