The human Z-type alpha(1)-antitrypsin variant has a strong tendency to accumulate folding intermediates due to extremely slow protein folding within the endoplasmic reticulum (ER) of hepatocytes. Human alpha(1)-antitrypsin has 17 peptidyl-prolyl bonds per molecule; thus, the effect of peptidyl-prolyl isomerases on Z-type alpha(1)-antitrypsin protein folding was analyzed in this study. The protein level of Cpr2p, a yeast ER peptidyl-prolyl isomerase, increased more than two-fold in Z-type alpha(1)-antitrypsin-expressing yeast cells compared to that in wild-type alpha(1)-antitrypsin-expressing cells. When CPR2 was deleted from the yeast genome, the cytotoxicity of Z-type alpha(1)-antitrypsin increased significantly. The interaction between Z-type alpha(1)-antitrypsin and Cpr2p was confirmed by co-immunoprecipitation. In vitro folding assays showed that Cpr2p facilitated Z-type alpha(1)-antitrypsin folding into the native state. Furthermore, Cpr2p overexpression significantly increased the extracellular secretion of Z-type alpha(1)-antitrypsin. Our results indicate that ER peptidyl-prolyl isomerases may rescue Z-type alpha(1)-antitrypsin molecules from retarded folding and eventually relieve clinical symptoms caused by this pathological alpha(1)-antitrypsin. (C) 2014 Elsevier Inc. All rights reserved.