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Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070386/ https://www.ncbi.nlm.nih.gov/pubmed/24909901 http://dx.doi.org/10.1016/j.devcel.2014.04.033 |
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author | Polishchuk, Elena V. Concilli, Mafalda Iacobacci, Simona Chesi, Giancarlo Pastore, Nunzia Piccolo, Pasquale Paladino, Simona Baldantoni, Daniela van IJzendoorn, Sven C.D. Chan, Jefferson Chang, Christopher J. Amoresano, Angela Pane, Francesca Pucci, Piero Tarallo, Antonietta Parenti, Giancarlo Brunetti-Pierri, Nicola Settembre, Carmine Ballabio, Andrea Polishchuk, Roman S. |
author_facet | Polishchuk, Elena V. Concilli, Mafalda Iacobacci, Simona Chesi, Giancarlo Pastore, Nunzia Piccolo, Pasquale Paladino, Simona Baldantoni, Daniela van IJzendoorn, Sven C.D. Chan, Jefferson Chang, Christopher J. Amoresano, Angela Pane, Francesca Pucci, Piero Tarallo, Antonietta Parenti, Giancarlo Brunetti-Pierri, Nicola Settembre, Carmine Ballabio, Andrea Polishchuk, Roman S. |
author_sort | Polishchuk, Elena V. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4070386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40703862014-06-26 Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis Polishchuk, Elena V. Concilli, Mafalda Iacobacci, Simona Chesi, Giancarlo Pastore, Nunzia Piccolo, Pasquale Paladino, Simona Baldantoni, Daniela van IJzendoorn, Sven C.D. Chan, Jefferson Chang, Christopher J. Amoresano, Angela Pane, Francesca Pucci, Piero Tarallo, Antonietta Parenti, Giancarlo Brunetti-Pierri, Nicola Settembre, Carmine Ballabio, Andrea Polishchuk, Roman S. Dev Cell Article 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. Cell Press 2014-06-23 /pmc/articles/PMC4070386/ /pubmed/24909901 http://dx.doi.org/10.1016/j.devcel.2014.04.033 Text en © 2014 The Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Polishchuk, Elena V. Concilli, Mafalda Iacobacci, Simona Chesi, Giancarlo Pastore, Nunzia Piccolo, Pasquale Paladino, Simona Baldantoni, Daniela van IJzendoorn, Sven C.D. Chan, Jefferson Chang, Christopher J. Amoresano, Angela Pane, Francesca Pucci, Piero Tarallo, Antonietta Parenti, Giancarlo Brunetti-Pierri, Nicola Settembre, Carmine Ballabio, Andrea Polishchuk, Roman S. Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis |
title | Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis |
title_full | Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis |
title_fullStr | Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis |
title_full_unstemmed | Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis |
title_short | Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis |
title_sort | wilson disease protein atp7b utilizes lysosomal exocytosis to maintain copper homeostasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070386/ https://www.ncbi.nlm.nih.gov/pubmed/24909901 http://dx.doi.org/10.1016/j.devcel.2014.04.033 |
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