Abstract
Accumulation of misfolded human Z-type alpha1-antitrypsin protein in the endoplasmic reticulum (ER) leads to persistent ER stress and subsequent cell death, leading to liver cirrhosis. When a Saccharomyces cerevisiae ORF-deletion library was screened for the response elements to accumulation of misfolded Z-type alpha1-antitrypsin protein, several deletion mutants of redox regulator genes aggravated Z-type alpha1-antitrypsin-induced cytotoxicity. Overexpression of Z-type alpha1-antitrypsin in yeasts caused cellular oxidative stress, when assessed by dichlorofluorescein assays. Z-type alpha1-antitrypsin-producing cells became vulnerable to further oxidative challenges with low concentrations of hydrogen peroxide. Protective effects from Z-type alpha1-antitrypsin-induced cytotoxicity of antioxidant chemicals, such as ascorbic acid, N-acetylcysteine, or butylated hydroxyanisole, were also evaluated. Our data add further example of oxidative stress caused by misfolded proteins, as in several human degenerative protein-misfolding diseases, including Alzheimer's, Huntington's, and Parkinson's diseases. The results also provide insight on cellular defense mechanism against protein folding problems and suggest future therapeutic applications.
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