title: 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 trafficking and site of action of ATP7B are subjects 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(+) through lysosomal-mediated exocytosis at the bile canaliculus. Here, we show that ATP7B is transported from the trans-Golgi network (TGN) 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 reveal the pathway of the Cu(+)-mediated transport of ATP7B from the TGN to the bile canaliculus and indicates that the bile canaliculus is the primary site of ATP7B action in the elimination of excess Cu(.)
authors.affiliation: Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Lalioti
authors.affiliation: Department of Genomics and Massive Sequencing, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Peiró
authors.affiliation: Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Manuela
authors.identifier: 0000-0001-8129-0107
authors.initials: M
authors.lastname: Pérez-Berlanga
authors.affiliation: Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Yo
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Department of Optical and Confocal Microscopy, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Muñoz
authors.affiliation: Department of Optical and Confocal Microscopy, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Villalba
authors.affiliation: Department of Optical and Confocal Microscopy, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid 28049, Spain isandoval@cbm.csic.es.
authors.forename: Ignacio V
authors.identifier: 0000-0003-1485-2936
authors.initials: IV
authors.lastname: Sandoval
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001648:Bile Canaliculi / Q000187:drug effects / Q000378:metabolism*; D020126:Brefeldin A / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism*; D002451:Cell Compartmentation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003300:Copper / Q000494:pharmacology*; D000073840:Copper-Transporting ATPases; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects*; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D018942:Macrolides; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D020126:Brefeldin A; D003300:Copper; C040929:bafilomycin A1; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases
keywords: ATP7B; Bile canaliculus; Copper; TGN; Trafficking; Transcytosis