Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha.
Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha.
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发表时间：
2005
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通讯作者：
X. Xue;Jiang-Hu Piao;A. Nakajima;S. Sakon-Komazawa;Y. Kojima;K. Mori;H. Yagita;K. Okumura;H. Harding;H. Nakano
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作者：
X. Xue;Jiang-Hu Piao;A. Nakajima;S. Sakon-Komazawa;Y. Kojima;K. Mori;H. Yagita;K. Okumura;H. Harding;H. Nakano
内质网(ER)中未折叠蛋白的积累导致内质网超载，导致内质网应激。为了应对内质网应激，哺乳动物细胞会触发一种称为未折叠蛋白反应(UPR)的特殊反应。虽然最近的研究表明内质网应激和氧化应激之间存在相互作用，但机制上的联系并不完全清楚。通过使用小鼠纤维肉瘤L929细胞，在肿瘤坏死因子(TNF)α诱导活性氧物种(ROS)积累和细胞死亡的情况下，我们证明了TNFα以ROS依赖的方式诱导UPR。与肿瘤坏死因子α不同的是，过氧化氢或亚砷酸盐的氧化应激只诱导真核溶解起始因子2α的磷酸化，而不能激活依赖于PERK或IRE1的通路，这表明不同的氧化应激诱导下游信号转导的特异性。相反，衣霉素诱导的UPR通过抑制细胞谷胱甘肽水平的降低，显著抑制了TNFα诱导的ROS积聚和细胞死亡。总体而言，部分(但不是全部)氧化应激诱导UPR，先发制人的UPR抵消了TNFpha诱导的ROS积累。
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER overload, resulting in ER stress. To cope with ER stress, mammalian cells trigger a specific response known as the unfolded protein response (UPR). Although recent studies have indicated cross-talk between ER stress and oxidative stress, the mechanistic link is not fully understood. By using murine fibrosarcoma L929 cells, in which tumor necrosis factor (TNF) alpha induces accumulation of reactive oxygen species (ROS) and cell death, we show that TNFalpha induces the UPR in a ROS-dependent fashion. In contrast to TNFalpha, oxidative stresses by H2O2 or arsenite only induce eukaroytic initiation factor 2alpha phosphorylation, but not activation of PERK- or IRE1-dependent pathways, indicating the specificity of downstream signaling induced by various oxidative stresses. Conversely, the UPR induced by tunicamycin substantially suppresses TNFalpha-induced ROS accumulation and cell death by inhibiting reduction of cellular glutathione levels. Collectively, some, but not all, oxidative stresses induce the UPR, and pre-emptive UPR counteracts TNFalpha-induced ROS accumulation.