title: Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.
abstract: Copper is an essential yet toxic metal and its overload causes Wilson disease, a disorder due to mutations in copper transporter ATP7B. To remove excess copper into the bile, ATP7B traffics toward canalicular area of hepatocytes. However, the trafficking mechanisms of ATP7B remain elusive. Here, we show that, in response to elevated copper, ATP7B moves from the Golgi to lysosomes and imports metal into their lumen. ATP7B enables lysosomes to undergo exocytosis through the interaction with p62 subunit of dynactin that allows lysosome translocation toward the canalicular pole of hepatocytes. Activation of lysosomal exocytosis stimulates copper clearance from the hepatocytes and rescues the most frequent Wilson-disease-causing ATP7B mutant to the appropriate functional site. Our findings indicate that lysosomes serve as an important intermediate in ATP7B trafficking, whereas lysosomal exocytosis operates as an integral process in copper excretion and hence can be targeted for therapeutic approaches to combat Wilson disease.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Polishchuk
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Concilli
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Iacobacci
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Chesi
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Pastore
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Piccolo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples 80125, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Paladino
authors.affiliation: University of Salerno, Fisciano (SA) 84084, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Baldantoni
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen 9713, the Netherlands.
authors.forename: Sven C D
authors.initials: SC
authors.lastname: van IJzendoorn
authors.affiliation: Department of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Jefferson
authors.initials: J
authors.lastname: Chan
authors.affiliation: Department of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Amoresano
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pane
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Pucci
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Tarallo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Medical Genetics, Department of Translational and Medical Sciences, Federico II University, Naples 80125, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Medical Genetics, Department of Translational and Medical Sciences, Federico II University, Naples 80125, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Medical Genetics, Department of Translational and Medical Sciences, Federico II University, Naples 80125, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Dulbecco Telethon Institute, TIGEM, Naples 80131, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Medical Genetics, Department of Translational and Medical Sciences, Federico II University, Naples 80125, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy. Electronic address: polish@tigem.it.
authors.forename: Roman S
authors.initials: RS
authors.lastname: Polishchuk
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D001646:Bile / Q000378:metabolism; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D000072159:Dynactin Complex; D005089:Exocytosis / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D027682:Cation Transport Proteins; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C484068:Tcfeb protein, mouse; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases