Inhibition of intracellular degradation increases secretion of a mutant form of α1-antitrypsin associated with profound deficiency

Abstract

The mutant Z form of α1-antitrypsin (α1AT) is responsible for > 95% of all individuals with α1AT deficiency, an important inherited cause of emphysema and liver disease. Since secreted Z α1AT is a functional antiprotease, we hypothesized that interrupting catabolism of retained Z α1AT might increase its transport out of cells, causing an increase in extracellular protease protection. Both the protein translation inhibitor cycloheximide and the specific inhibitor of proteasome function, lactacystin, prevented intracellular degradation of Z α1AT. Moreover, this inhibition of degradation was associated with partial restoration of Z α1AT vesicular transport. This effect was observed in a model system of transfected CHO cells as well as in human alveolar macrophages synthesizing Z α1AT. This study supports the hypothesis that altering the intracellular fate of a mutant protein may be an option in the treatment of diseases associated with misfolded but potentially functional proteins.