title: Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants.
abstract: Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The ATP7B gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans-Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several ATP7B mutations, including H1069Q and R778L that are two of the most frequent variants, result in protein products, which, although still functional, remain in the endoplasmic reticulum. Thus, they fail to reach Cu excretion sites, resulting in the toxic buildup of Cu in the liver of WD patients. Therefore, correcting the location of these mutants by leading them to the appropriate functional sites in the cell should restore Cu excretion and would be beneficial to help large cohorts of WD patients. However, molecular targets for correction of endoplasmic reticulum-retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c-Jun N-terminal kinase signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNA interference or specific chemical inhibitors results in the substantial rescue of ATP7B(H1069Q) (as well as that of several other WD-causing mutants) from the endoplasmic reticulum to the trans-Golgi network compartment, in recovery of its Cu-dependent trafficking, and in reduction of intracellular Cu levels.
  
  
  
  Our findings indicate p38 and c-Jun N-terminal kinase as intriguing targets for correction of WD-causing mutants and, hence, as potential candidates, which could be evaluated for the development of novel therapeutic strategies to combat WD. (Hepatology 2016;63:1842-1859).
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Chesi
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Ramanath N
authors.initials: RN
authors.lastname: Hegde
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Iacobacci
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Concilli
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Parashuraman
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Beatrice Paola
authors.initials: BP
authors.lastname: Festa
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Polishchuk
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Tullio
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Carissimo
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Montefusco
authors.affiliation: CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Canetti
authors.affiliation: CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Monti
authors.affiliation: CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Amoresano
authors.affiliation: CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Pucci
authors.affiliation: Molecular Genetics Section of Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: Department of Physiology, Johns Hopkins University, Baltimore, MD.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.|Istituto di Ricovero e Cura a Carattere Scientifico SDN, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Roman S
authors.initials: RS
authors.lastname: Polishchuk
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D006367:HeLa Cells; D056945:Hep G2 Cells; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009154:Mutation; D055571:Secretory Pathway
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases