Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.
Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.
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DOI：
10.1016/j.devcel.2014.04.033
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发表时间：
2014-06-23
影响因子：
11.8
通讯作者：
Polishchuk, Roman S.
中科院分区：
文献类型：
--
作者：
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.
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. ATP7B moves from the Golgi to lysosomes in response to elevated copper levels ATP7B promotes storage of copper in lysosomal lumen By interacting with p62/dynactin, ATP7B promotes polarized exocytosis of lysosomes Lysosomal exocytosis allows hepatocytes to release excess copper into the bile Mutations in the copper transporter ATP7B cause copper overload and toxicity in Wilson disease. Polishchuk et al. show that copper overload induces ATP7B transfer from the Golgi to lysosomes, where ATP7B sequesters excess metal in the lumen and, via interaction with dynactin, promotes copper exocytosis from hepatocytes into bile.
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DOI：
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影响因子：
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