TY - JOUR
T1 - Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis
AU - Polishchuk, Elena V.
AU - Concilli, Mafalda
AU - Iacobacci, Simona
AU - Chesi, Giancarlo
AU - Pastore, Nunzia
AU - Piccolo, Pasquale
AU - Paladino, Simona
AU - Baldantoni, Daniela
AU - vanIJzendoorn, Sven C.D.
AU - Chan, Jefferson
AU - Chang, Christopher J.
AU - Amoresano, Angela
AU - Pane, Francesca
AU - Pucci, Piero
AU - Tarallo, Antonietta
AU - Parenti, Giancarlo
AU - Brunetti-Pierri, Nicola
AU - Settembre, Carmine
AU - Ballabio, Andrea
AU - Polishchuk, Roman S.
N1 - Funding Information:
This work was supported by grants from Italian Telethon Foundation (TGM11CB4 to R.S.P., TGM11SB1 to A.B., P37TELC to N.B.-P., and TCP12008 to C.S.), AIRC (IG 10233 to R.S.P.), ERC (250154 to A.B. and IEMTx to N.B.-P.), March of Dimes (no. 6-FY11-306 to A.B.), and NIH (R01-NS078072 to A.B.). C.J.C. is an Investigator with the Howard Hughes Medical Institute and thanks support from the NIH (GM 79465). G.C. and J.C. were supported by a fellowship from POR Campania and HFSP, respectively. We would like to acknowledge support from Associazione Nazionale Malattia di Wilson and everybody who provided us with antibodies, reagents, and cells. We would like to thank Svetlana Lutsenko, Graciana Diez-Roux, and Antonella De Matteis for critical reading of the manuscript, TIGEM Advanced Microscopy and Imaging Core for microscopy support, and TIGEM Vector Core for production of adenoviruses.
PY - 2014/6/23
Y1 - 2014/6/23
N2 - 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.
AB - 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.
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U2 - 10.1016/j.devcel.2014.04.033
DO - 10.1016/j.devcel.2014.04.033
M3 - Article
C2 - 24909901
AN - SCOPUS:84904672562
SN - 1534-5807
VL - 29
SP - 686
EP - 700
JO - Developmental cell
JF - Developmental cell
IS - 6
ER -