Matsuo Yoshiyuki, Hirota Kiichi
Department of Human Stress Response Science Institute of Biomedical Science Kansai Medical University Japan.
FEBS Open Bio. 2017 Oct 3;7(11):1768-1777. doi: 10.1002/2211-5463.12319. eCollection 2017 Nov.
Numerous secretory and membrane proteins undergo post-translational modifications in the endoplasmic reticulum (ER), and the formation of disulfide bonds is a modification that is critical for proper protein folding. The mammalian ER contains a large family of oxidoreductases that are considered to catalyze thiol/disulfide exchange and ensure the maintenance of a redox environment within the ER. Disruption of ER homeostasis causes an accumulation of misfolded and unfolded proteins, a condition termed ER stress. Despite advances in our understanding of the ER stress response and its downstream signaling pathway, it remains unclear how ER redox balance is controlled and restored in the stressed ER. In this study, we determined that brefeldin A (BFA)-induced protein accumulation in the ER triggers reversible oxidation of transmembrane thioredoxin-related protein 1 (TMX1). Conversion of TMX1 to the oxidized state preceded the induction of immunoglobulin-binding protein, a downstream marker of ER stress. Oxidized TMX1 reverted to the basal reduced state after BFA removal, and our results suggest that glutathione is involved in maintaining TMX1 in the reduced form. These findings provide evidence for a redox imbalance caused by protein overload, and demonstrate the existence of a pathway that helps restore ER homeostasis during poststress recovery.
许多分泌蛋白和膜蛋白在内质网（ER）中经历翻译后修饰，二硫键的形成是一种对蛋白质正确折叠至关重要的修饰。哺乳动物内质网含有一大类氧化还原酶，它们被认为催化硫醇/二硫键交换，并确保内质网内氧化还原环境的维持。内质网稳态的破坏会导致错误折叠和未折叠蛋白的积累，这种情况被称为内质网应激。尽管我们对内质网应激反应及其下游信号通路的理解取得了进展，但尚不清楚在内质网应激状态下，内质网氧化还原平衡是如何被控制和恢复的。在这项研究中，我们确定布雷菲德菌素A（BFA）诱导的内质网蛋白积累会触发跨膜硫氧还蛋白相关蛋白1（TMX1）的可逆氧化。TMX1向氧化态的转变先于内质网应激下游标志物免疫球蛋白结合蛋白的诱导。BFA去除后，氧化的TMX1恢复到基础还原状态，我们的结果表明谷胱甘肽参与将TMX1维持在还原形式。这些发现为蛋白质过载导致的氧化还原失衡提供了证据，并证明存在一条有助于在内质网应激后恢复过程中恢复内质网稳态的途径。
