Antioxidant Responses are Crucial for Defense against Misfolded Human Z-Type α1-Antitrypsin

The Z-type variant of human α1-antitrypsin is involved in liver cirrhosis and pulmonary emphysema. Due to its slow folding characteristics, this variant accumulates folding intermediates and forms protein aggregates within hepatocytes. Misfolded proteins may induce oxidative stress and subsequent cell death.The potential application of antioxidant response signaling pathway and antioxidants to cope with Z-type α1-antitrypsin-induced oxidative stress was evaluated.Overexpression of Z-type α1-antitrypsin in Saccharomyces cerevisiae provoked oxidative stress and increased susceptibility to oxidative challenges such as hydrogen peroxide treatment. Deletion of antioxidant-response genes, including yap1, skn7, sod2, tsa1, and pst2, exacerbated the slow growth phenotype of Z-type α1-antitrypsin-expressing cells. Antioxidant treatment alleviated oxidative stress and cytotoxicity induced by Z-type α1-antitrypsin.Our results show that cellular antioxidant capacity is crucial to protection against misfolded Z-type α1-antitrypsin.The information obtained here may be used to prevent oxidative stress caused by misfolded proteins, which are associated with several degenerative diseases, including amyotrophic lateral sclerosis and Parkinson's disease.