Activation of JNK pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin

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 SERPINA1 gene resulting in a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Therefore, the liver disease is caused by a gain of function mechanism due to accumulation of the mutant Z alpha1-antitrypsin (ATZ) and is a key example of an important 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 JNK and c-JUN and genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c-JUN mediated SERPINA1 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 (iPSCs)-hepatic cells with a JNK inhibitor reduced accumulation of ATZ. In conclusion, 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. This article is protected by copyright. All rights reserved.