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Reinforcement of the Unfolded Protein Response Mitigates Cytotoxicity Induced by Human Z‐Type α 1 ‐Antitrypsin
Author(s) -
Lim Jaeyeon,
Lee Kyunghee,
Im Hana
Publication year - 2021
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.12289
Subject(s) - unfolded protein response , endoplasmic reticulum , secretion , protein folding , chemistry , extracellular , protein engineering , cell , cytotoxicity , microbiology and biotechnology , phenotype , biology , in vitro , biochemistry , enzyme , gene
Deficient human α 1 ‐antitrypsin (AAT) variants are involved in pulmonary emphysema and liver cirrhosis. Especially, the Z‐type AAT (Z AAT) variant folds very slowly, and thus accumulates protein folding intermediates prone to aggregation in the endoplasmic reticulum (ER) of hepatocytes. Misfolded proteins accumulated in the ER lead to persistent ER stress and subsequent cell death. In this study, the contribution of unfolded protein response (UPR) in Z AAT‐induced cytotoxicity was investigated. Deletions of each UPR element severely hampered growth of Z AAT‐overexpressing yeast cells. Overexpression of UPR elements, except kar2 , alleviated the slow growth phenotype of Z AAT‐overexpressing cells, possibly through augmentation of folding capacity. Furthermore, reinforcement of UPR elements promoted extracellular secretion of Z AAT, which may have mitigated the plasma deficiency of AAT. Our results therefore provide further information on therapeutic strategies to address protein folding diseases.