title: Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin.
abstract: Alpha1-antitrypsin deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the serine protease inhibitor 1A (SERPINA1) gene leading to a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Alpha1-antitrypsin defciency-related liver disease is therefore caused by a gain-of-function mechanism due to accumulation of the mutant Z alpha1-antitrypsin (ATZ) and is a key example of an disease mechanism induced by protein toxicity. Intracellular retention of ATZ triggers a complex injury cascade including apoptosis and other mechanisms, although several aspects of the disease pathogenesis are still unclear. We show that ATZ induces activation of c-Jun N-terminal kinase (JNK) and c-Jun and that genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c-Jun-mediated SERPINA1 gene expression. JNK activation was confirmed in livers of patients homozygous for the Z allele, with severe liver disease requiring hepatic transplantation. Treatment of patient-derived induced pluripotent stem cell-hepatic cells with a JNK inhibitor reduced accumulation of ATZ.
  
  
  
  These data reveal that JNK is a key pathway in the disease pathogenesis and add new therapeutic entry points for liver disease caused by ATZ. (Hepatology 2017;65:1865-1874).
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Pastore
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Attanasio
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.|Department of Translational Medicine, Federico II University, Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Granese
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Castello
authors.affiliation: Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, Saint Louis, MO, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Teckman
authors.affiliation: Boston University Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX.|Department of Translational Medicine, Federico II University, Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.|Department of Translational Medicine, Federico II University, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D048031:JNK Mitogen-Activated Protein Kinases