Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants.

Autor: Chesi G; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Hegde RN; Institute of Protein Biochemistry, National Research Council, Naples, Italy., Iacobacci S; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Concilli M; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Parashuraman S; Institute of Protein Biochemistry, National Research Council, Naples, Italy., Festa BP; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Polishchuk EV; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Di Tullio G; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Carissimo A; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Montefusco S; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Canetti D; CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy., Monti M; CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy., Amoresano A; CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy., Pucci P; CEINGE and Department of Chemical Sciences, Federico II University, Naples, Italy., van de Sluis B; Molecular Genetics Section of Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Lutsenko S; Department of Physiology, Johns Hopkins University, Baltimore, MD., Luini A; Institute of Protein Biochemistry, National Research Council, Naples, Italy.; Istituto di Ricovero e Cura a Carattere Scientifico SDN, Naples, Italy., Polishchuk RS; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2016 Jun; Vol. 63 (6), pp. 1842-59. Date of Electronic Publication: 2016 Jan 25.
DOI: 10.1002/hep.28398
Abstrakt: Unlabelled: 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.
Conclusion: 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).
(© 2015 by The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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