Antioxidants reduce endoplasmic reticulum stress and improve protein secretion
Antioxidants reduce endoplasmic reticulum stress and improve protein secretion
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DOI：
10.1073/pnas.0809677105
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发表时间：
2008-11-25
影响因子：
11.1
通讯作者：
Kaufman, Randal J.
中科院分区：
文献类型：
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作者：
Malhotra, Jyoti D.;Miao, Hongzhi;Kaufman, Randal J.
内质网(ER)中的蛋白质错误折叠导致了许多疾病的发生。虽然氧化应激可以破坏蛋白质折叠，但蛋白质错误折叠和氧化应激是如何相互影响的还没有被探索。我们分析了血友病A中缺失的凝血因子VIII(FVIII)的表达，以阐明蛋白质错误折叠与氧化应激的关系。新合成的FVIII在内质网管腔内错误折叠，激活未折叠蛋白反应(UPR)，导致氧化应激，并在体外和体内诱导小鼠细胞凋亡。值得注意的是，在体外和体内，抗氧化治疗减少了UPR的激活、氧化应激和细胞凋亡，并增加了FVIII的分泌。这些发现表明，活性氧物种是内质网中错误折叠的蛋白质产生的信号，导致UPR激活和细胞死亡。减少活性氧的基因或化学干预可以改善蛋白质折叠和细胞存活，并可能提供一种治疗和/或预防蛋白质错误折叠疾病的途径。
Protein misfolding in the endoplasmicc 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.