Factor VIII Biosynthesis and the Unfolded Protein Response.

Abstract SCI-19

Factor VIII is the protein deficient in the × chromosome-linked bleeding disorder hemophilia A. Previous studies demonstrated that FVIII expression in mammalian cells is limited due to protein misfolding of the newly synthesized polypeptide in the lumen of the endoplasmic reticulum (ER). 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 FVIII to elucidate the relationship between protein misfolding and oxidative stress. Accumulation of misfolded FVIII in the lumen of the ER 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.