Owing to their capability to disrupt the oxidative protein folding environment in the endoplasmic reticulum (ER), thiol antioxidants, such as dithiothreitol (DTT), are used as ER-specific stressors. We recently showed that thiol antioxidants modulate the methionine-homocysteine cycle by upregulating an S-adenosylmethionine-dependent methyltransferase, rips-1, in Caenorhabditis elegans. However, the changes in cellular physiology induced by thiol stress that modulate the methionine-homocysteine cycle remain uncharacterized. Here, using forward genetic screens in C. elegans, we discover that thiol stress enhances rips-1 expression via the hypoxia response pathway. We demonstrate that thiol stress activates the hypoxia response pathway. The activation of the hypoxia response pathway by thiol stress is conserved in human cells. The hypoxia response pathway enhances thiol toxicity via rips-1 expression and confers protection against thiol toxicity via rips-1-independent mechanisms. Finally, we show that DTT might activate the hypoxia response pathway by producing hydrogen sulfide. Our studies reveal an intriguing interaction between thiol-mediated reductive stress and the hypoxia response pathway and challenge the current model that thiol antioxidant DTT disrupts only the ER milieu in the cell.

中文翻译：

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硫醇还原应激激活缺氧反应途径

由于硫醇抗氧化剂能够破坏内质网 (ER) 中的氧化蛋白折叠环境，例如二硫苏糖醇 (DTT)，因此被用作 ER 特异性应激源。我们最近表明，硫醇抗氧化剂通过上调秀丽隐杆线虫中的 S-腺苷甲硫氨酸依赖性甲基转移酶rips-1来调节甲硫氨酸-同型半胱氨酸循环。然而，由调节蛋氨酸-同型半胱氨酸循环的硫醇应激引起的细胞生理学变化仍然未知。在这里，通过在线虫中进行正向遗传筛选，我们发现硫醇应激通过缺氧反应途径增强rips-1 的表达。我们证明硫醇应激激活缺氧反应途径。硫醇应激对缺氧反应途径的激活在人类细胞中是保守的。缺氧反应途径通过rips-1表达增强硫醇毒性，并通过rips-1独立机制提供针对硫醇毒性的保护。最后，我们表明 DTT 可能通过产生硫化氢来激活缺氧反应途径。我们的研究揭示了硫醇介导的还原应激与缺氧反应途径之间有趣的相互作用，并挑战了当前的模型，即硫醇抗氧化剂 DTT 仅破坏细胞中的 ER 环境。