Basolateral sorting and transcytosis define the Cu+-regulated translocation of ATP7B to the bile canaliculus

Abstract

The Cu+ pump ATP7B plays an irreplaceable role in the elimination of excess Cu+ by the hepatocyte into the bile. The traffic and site of ATP7B action is a subject of controversy. One current proposal is that an increase in intracellular Cu+ results in the translocation of ATP7B to the lysosomes and excretion of excess Cu+ by lysosomal mediated exocytosis at the bile canaliculus. Here we show that ATP7B is transported from the trans-Golgi network to the bile canaliculus by basolateral sorting and endocytosis, and microtubule mediated transcytosis through the subapical compartment. Trafficking ATP7B is not incorporated into lysosomes and addition of Cu+ does not cause relocalization of lysosomes and the appearance of lysosome markers in the bile canaliculus. Our data describes the pathway of the Cu+-mediated transport of ATP7B from the TGN to the bile canaliculus and indicates that the bile canaliculus is the prime site of ATP7B action in the elimination of excess Cu+.