Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis

Elena V. Polishchuk, Mafalda Concilli, Simona Iacobacci, Giancarlo Chesi, Nunzia Pastore, Pasquale Piccolo, Simona Paladino, Daniela Baldantoni, Sven C.D. vanIJzendoorn, Jefferson Chan, Christopher J. Chang, Angela Amoresano, Francesca Pane, Piero Pucci, Antonietta Tarallo, Giancarlo Parenti, Nicola Brunetti-Pierri, Carmine Settembre, Andrea Ballabio, Roman S. Polishchuk

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)686-700
Number of pages15
JournalDevelopmental cell
Volume29
Issue number6
DOIs
StatePublished - Jun 23 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Polishchuk, E. V., Concilli, M., Iacobacci, S., Chesi, G., Pastore, N., Piccolo, P., Paladino, S., Baldantoni, D., vanIJzendoorn, S. C. D., Chan, J., Chang, C. J., Amoresano, A., Pane, F., Pucci, P., Tarallo, A., Parenti, G., Brunetti-Pierri, N., Settembre, C., Ballabio, A., & Polishchuk, R. S. (2014). Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis. Developmental cell, 29(6), 686-700. https://doi.org/10.1016/j.devcel.2014.04.033