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

ABSTRACT: α₁-Antitrypsin (AAT) encoded by the SERPINA1 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 SERPINA1 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

SUBMITTER: Attanasio S 

PROVIDER: S-EPMC7504927 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature