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Dev Cell. 2014 Jun 23;29(6):686-700. doi: 10.1016/j.devcel.2014.04.033. Epub 2014 Jun 5.

Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.

Author information

1
Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
2
Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA.
3
Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples 80125, Italy.
4
University of Salerno, Fisciano (SA) 84084, Italy.
5
Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen 9713, the Netherlands.
6
Department of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
7
Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
8
Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy; Medical Genetics, Department of Translational and Medical Sciences, Federico II University, Naples 80125, Italy.
9
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.
10
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.
11
Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy. Electronic address: polish@tigem.it.

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.

PMID:
24909901
PMCID:
PMC4070386
DOI:
10.1016/j.devcel.2014.04.033
[Indexed for MEDLINE]
Free PMC Article
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