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

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 multi-transmembrane domain ATPase that traffics from the trans-Golgi network (TGN) 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 function remain in the endoplasmic reticulum (ER). Thus, they fail to reach Cu excretion sites, resulting in the toxic build-up 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 ER-retained ATP7B mutants remain elusive. Here we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and JNK signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNAi or specific chemical inhibitors results in the substantial rescue of ATP7BH1069Q (as well as that of several other WD-causing mutants) from the ER to the TGN compartment, in recovery of its Cu-dependent trafficking and in reduction of intracellular Cu levels. CONCLUSION: In summary, our findings indicate p38 and JNK 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. This article is protected by copyright. All rights reserved.