ArticleHepatology (Baltimore, Md.)2016
Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants.
Article in Hepatology (Baltimore, Md.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 57 citations in OpenAlex.
- Balancing cellular copper levels via the post-translational regulation of copper transport.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- Copper in Human Health and Disease: Insights from Inherited Disorders.Physiology (Bethesda, Md.) · 2026Review
- Clinical and genetic characterization of patients with late onset Wilson's disease.NPJ genomic medicine · 2024Article
- A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.Traffic (Copenhagen, Denmark) · 2024Article
- The Role of Copper Homeostasis in Brain Disease.International journal of molecular sciences · 2022Review
- Review
- Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China.Translational neurodegeneration · 2022Article
- Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system.Open biology · 2021Review
- Wilson's Disease: An Update on the Diagnostic Workup and Management.Journal of clinical medicine · 2021Review
- Inhibition of ASIC1a-Mediated ERS Improves the Activation of HSCs and Copper Transport Under Copper Load.Frontiers in pharmacology · 2021Article
- Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties.Scientific reports · 2020Article
- [Progress in molecular mechanism of hepatolenticular degeneration induced by ATP7B gene mutation].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2020Review
- Review
- Trafficking mechanisms of P-type ATPase copper transporters.Current opinion in cell biology · 2019Review
- Review
- Update on the Diagnosis and Management of Wilson Disease.Current gastroenterology reports · 2018Review
- An αB-Crystallin Peptide Rescues Compartmentalization and Trafficking Response to Cu Overload of ATP7B-H1069Q, the Most Frequent Cause of Wilson Disease in the Caucasian Population.International journal of molecular sciences · 2018Article
- Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells.Scientific reports · 2018Article
- The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2017Review
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18 authors at 6 institutions in 3 countries.
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Abstract
unlabelledWilson 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.
conclusionOur 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).
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