Antioxidants reduce endoplasmic reticulum stress and improve protein secretion

Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2008; 105(47):18525-30. DOI: 10.1073/pnas.0809677105
Source: PubMed

ABSTRACT Protein misfolding in the endoplasmic reticulum (ER) contributes to the pathogenesis of many diseases. Although oxidative stress can disrupt protein folding, how protein misfolding and oxidative stress impact each other has not been explored. We have analyzed expression of coagulation factor VIII (FVIII), the protein deficient in hemophilia A, to elucidate the relationship between protein misfolding and oxidative stress. Newly synthesized FVIII misfolds in the ER lumen, activates the unfolded protein response (UPR), causes oxidative stress, and induces apoptosis in vitro and in vivo in mice. Strikingly, antioxidant treatment reduces UPR activation, oxidative stress, and apoptosis, and increases FVIII secretion in vitro and in vivo. The findings indicate that reactive oxygen species are a signal generated by misfolded protein in the ER that cause UPR activation and cell death. Genetic or chemical intervention to reduce reactive oxygen species improves protein folding and cell survival and may provide an avenue to treat and/or prevent diseases of protein misfolding.

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Available from: Hongzhi Miao, Sep 15, 2014
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    • "In mammalian cells too, glutathione stands to impact the maturation of some secreted or membrane proteins: In a study agnostic of its enzymatic activity, over-expression of wild-type cytosolic ChaC1 in mouse ganglionic eminence cells profoundly inhibited the maturation of the Notch precursor to its furin-cleaved form (Chi et al., 2012). Whereas anti-oxidants that restore impaired glutathione metabolism to normality have been shown to improve the capacity of liver cells to secrete factor VIII, a heavily disulfide bonded serum protein (Malhotra et al., 2008). Thus, conservatively interpreted, our observations lead to the conclusion that ER glutathione is not generally required to maintain protein thiol redox nor folding homeostasis in the ER of cultured mammalian cells. "
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