title: Antioxidants reduce endoplasmic reticulum stress and improve protein secretion.
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.
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Jyoti D
authors.initials: JD
authors.lastname: Malhotra
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Miao
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
authors.forename: Anna
authors.initials: A
authors.lastname: Wolfson
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Steven W
authors.initials: SW
authors.lastname: Pipe
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011489:Protein Denaturation
chemical_list: D000975:Antioxidants; D005169:Factor VIII