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Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding αi‐antitrypsin transgenic mice
Author(s) -
Papp Eszter,
Száiraz Péter,
Korcsmáiros Tamás,
Csermely Peter
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5065fje
Subject(s) - endoplasmic reticulum , protein disulfide isomerase , unfolded protein response , chaperone (clinical) , genetically modified mouse , cytoplasm , transgene , protein folding , biochemistry , reductase , biology , chemistry , microbiology and biotechnology , enzyme , medicine , gene , pathology
Alpha1-antitrypsin (AAT) deficiency is characterized by the accumulation of the misfolded mutant, Z form of alpha1-antitrypsin (PiZ) inside the lumen of the hepatic endoplasmic reticulum (ER). Both human patients and PiZ transgenic mice have similar symptoms of hepatic failure culminating in cirrhosis and hepatocellular carcinoma. The involvement of molecular chaperones, as well as the relevance of oxidative stress in this disease is not characterized well yet. Here, we show that, in the PiZ transgenic mice, the 58-kDa protein disulfide isomerase (PDI), the most important oxidoreductase and chaperone of the endoplasmic reticulum, is in a complex with PiZ, which is accompanied by a decrease of protein disulfide reductase activity of the ER. PiZ transgenic mice have a shift toward a more reduced ER environment and an elevation of cytoplasmic chaperones and antioxidant enzymes. Our data suggest that lower availability of PDI and a decreased protein disulfide reductase activity of the ER along with a cytoplasmic stress may contribute to the toxic effects of PiZ aggregation.