ATP7B Copper-Regulated Traffic and Association With the Tight Junctions: Copper Excretion Into the Bile

Abstract

Whereas the ATP7B retained in the trans-Golgi-network is massively translocated to the bile canalicular membrane in response to increased copper levels, a pool of ATP7B associated with the tight junctions remains stable. In situ studies indicate that copper is excreted into the bile by 2 separate pathways. The results are discussed in the frame of the normal and impeded excretion of copper into the bile.

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

“…The inhibition of apical ATP7B endocytosis by DYN is consistent with the bile canaliculus being the site of ATP7B function in Cu + excretion. It should be noted that this finding confirms previous observations of Cu + -induced translocation of ATP7B from the TGN to the bile canaliculus in HepG2 cells and the localization of ATP7B in the bile canaliculus of liver (Guo et al, 2005;Roelofsen et al, 2000;Schaefer et al, 1999b), and that these studies have been subsequently confirmed in other cells by other laboratories (Guo et al, 2005;Hernandez et al, 2008).…”

“…S1A-D) (Cassio et al, 2007;Hernandez et al, 2008); this arrangement greatly facilitates monitoring the changes in the distribution of ATP7B in response to increased Cu + levels in the cell.…”

“…The detection of Cu + within lysosomes carrying ATP7B in their membranes and the increase in trafficking of ATP7B to the bile canaliculus upon activation of lysosomal exocytosis, together with the recent report that brief exposure to Cu + activates lysosomal exocytosis, has led to the proposal that ATP7B pumps excess Cu + into lysosomes and that the lysosomes loaded with Cu + then fuse with the membrane of the bile canaliculus (Polishchuk et al, 2014). These observations are in contrast with studies indicating that ATP7B is transported from the Golgi to the bile canaliculus (Guo et al, 2005;Hernandez et al, 2008;Roelofsen et al, 2000) and recent evidence indicating that transport to the bile canaliculus occurs through a trans-endosomal pathway (Lalioti et al, 2014;Nyasae et al, 2014).…”

“…However, although the direct relocalization of ATP7B to the bile canaliculus would appear to be the most likely trafficking route, studies on the Cu + -induced relocation of ATP7B have resulted in identification of other membrane targets, including late endosomes and lysosomes (Harada et al, 2003a;Polishchuk et al, 2014;Weiss et al, 2008). In addition, a stable pool of ATP7B has been located at tight junctions (Hernandez et al, 2008). The detection of Cu + within lysosomes carrying ATP7B in their membranes and the increase in trafficking of ATP7B to the bile canaliculus upon activation of lysosomal exocytosis, together with the recent report that brief exposure to Cu + activates lysosomal exocytosis, has led to the proposal that ATP7B pumps excess Cu + into lysosomes and that the lysosomes loaded with Cu + then fuse with the membrane of the bile canaliculus (Polishchuk et al, 2014).…”

Posttranslational regulation of copper transporters

“…A certain degree of homology within this region is present between ATP7A and ATP7B, but it is currently unknown whether transmembrane helix 3 in ATP7B contains a similar TGNtargeting signal. Recent studies localized ATP7B to tight junctions in hepatocytes, where it might be involved in paracellular copper transport [63]. Taken together, the general consensus is that ATP7A and ATP7B are localized in the TGN under basal copper conditions.…”