CHOP and c-JUN up-regulate the mutant Z α1-antitrypsin, exacerbating its aggregation and liver proteotoxicity

Abstract

α₁-Antitrypsin (AAT) encoded by the <i>SERPINA1</i> gene is an acute-phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of <i>SERPINA1</i> encodes a mutant AAT, named ATZ, that changes the protein structure and leads to its misfolding and polymerization, which cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a loss-of-function mechanism. The pathogenetic mechanisms underlying the liver disease are not completely understood. C/EBP-homologous protein (CHOP), a transcription factor induced by ER stress, was found among the most up-regulated genes in livers of PiZ mice that express ATZ and in human livers of patients homozygous for the Z allele. Compared with controls, juvenile PiZ/<i>Chop</i>^-/- mice showed reduced hepatic ATZ and a transcriptional response indicative of decreased ER stress by RNA-Seq analysis. Livers of PiZ/<i>Chop</i>^-/- mice also showed reduced <i>SERPINA1</i> mRNA levels. By chromatin immunoprecipitations and luciferase reporter-based transfection assays, CHOP was found to up-regulate <i>SERPINA1</i> cooperating with c-JUN, which was previously shown to up-regulate <i>SERPINA1</i>, thus aggravating hepatic accumulation of ATZ. Increased <i>CHOP</i> levels were detected in diseased livers of children homozygous for the Z allele. In summary, CHOP and c-JUN up-regulate <i>SERPINA1</i> transcription and play an important role in hepatic disease by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.