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

The mutant Z form of alpha 1-antitrypsin (alpha 1AT) is responsible for > 95% of all individuals with alpha 1AT deficiency, an important inherited cause of emphysema and liver disease. Since secreted Z alpha 1AT is a functional antiprotease, we hypothesized that interrupting catabolism of retained Z alpha 1AT 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 alpha 1AT, Moreover, this inhibition of degradation was associated with partial restoration of Z alpha 1AT vesicular transport. This effect was observed in a model system of transfected CHO cells as well as in human alveolar macrophages synthesizing Z alpha 1AT. 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.