{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:54:09Z","timestamp":1790992449366,"version":"4.1.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2016,1,25]],"date-time":"2016-01-25T00:00:00Z","timestamp":1453680000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The <jats:italic toggle=\"yes\">ATP7B<\/jats:italic> gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans\u2010Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several <jats:italic toggle=\"yes\">ATP7B<\/jats:italic> 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\u2010retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c\u2010Jun N\u2010terminal 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<jats:sup>H1069Q<\/jats:sup> (as well as that of several other WD\u2010causing mutants) from the endoplasmic reticulum to the trans\u2010Golgi network compartment, in recovery of its Cu\u2010dependent trafficking, and in reduction of intracellular Cu levels. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our findings indicate p38 and c\u2010Jun N\u2010terminal kinase as intriguing targets for correction of WD\u2010causing mutants and, hence, as potential candidates, which could be evaluated for the development of novel therapeutic strategies to combat WD. (H<jats:sc>epatology<\/jats:sc> 2016;63:1842\u20101859)<\/jats:p>","DOI":"10.1002\/hep.28398","type":"journal-article","created":{"date-parts":[[2015,12,14]],"date-time":"2015-12-14T04:38:48Z","timestamp":1450067928000},"page":"1842-1859","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Identification of p38 MAPK and JNK as new targets for correction of Wilson disease\u2010causing ATP7B mutants"],"prefix":"10.1097","volume":"63","author":[{"given":"Giancarlo","family":"Chesi","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanath N.","family":"Hegde","sequence":"additional","affiliation":[{"name":"Institute of Protein Biochemistry,National Research 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