Activation of transcription factor Nrf2 by hepatitis C virus induces the cell-survival pathway (Publication with Expression of Concern. See vol. 100, pg. 1341, 2019) (Retracted article. See vol. 100, pg. 1715, 2019)
Activation of transcription factor Nrf2 by hepatitis C virus induces the cell-survival pathway (Publication with Expression of Concern. See vol. 100, pg. 1341, 2019) (Retracted article. See vol. 100, pg. 1715, 2019)
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DOI：
10.1099/vir.0.014340-0
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发表时间：
2010-03-01
影响因子：
3.8
通讯作者：
Waris, Gulam
中科院分区：
文献类型：
--
作者：
Burdette, Dylan;Olivarez, Mathew;Waris, Gulam
氧化应激与多种人类疾病有关，包括丙型肝炎病毒（HCV）的发病机制。先前的研究表明，表达 HCV 基因的培养细胞会诱导氧化应激。已知转录因子 Nrf2 在氧化应激反应中被激活，但其激活机制尚不清楚。在本研究中，我们首先确定了Nrf2的诱导，然后研究了感染HCV（JFH-1）的人肝癌细胞中Nrf2激活的机制。我们的结果显示 Nrf2 的诱导和核转位具有时间依赖性。在抗氧化剂 PDTC（吡咯烷二硫代氨基甲酸酯）和 Ca2+ 螯合剂 BAPTA-AM [1,2-双（氨基苯氧基）乙烷 N,N,N,N-四乙酸四（乙酰氧基甲基）酯] 存在下，HCV 介导的 Nrf2 激活被消除，这表明活性氧和 Ca2+ 信号在 Nrf2 激活过程中发挥作用。通过使用细胞激酶抑制剂，我们进一步表明，HCV 介导的 Nrf2 磷酸化/激活是由丝裂原激活蛋白 (MAP) 激酶 p38 MAPK 和 janus 激酶介导的。我们还观察到 HCV 感染细胞中 Akt 及其下游底物 Bad 的磷酸化增强。此外，通过使用小干扰RNA方法，我们的结果表明HCV介导的Nrf2激活在HCV感染细胞的存活中具有潜在作用，这是一种有利于肝脏肿瘤发生的条件。总之，这些结果提供了对HCV诱导与慢性HCV感染相关的细胞内事件的机制的深入了解。
Oxidative stress has been implicated in various human diseases, including the pathogenesis of hepatitis C virus (HCV). Previous studies have shown the induction of oxidative stress in cultured cells expressing HCV genes. The transcription factor Nrf2 is known to be activated in response to oxidative stress, but the mechanism of its activation is not clearly understood. In this study, we first determined the induction of Nrf2 and then investigated the mechanism of Nrf2 activation in human hepatoma cells infected with HCV (JFH-1). Our results showed the induction and nuclear translocation of Nrf2 in a time-dependent manner. The HCV-mediated activation of Nrf2 was abrogated in the presence of an antioxidant, PDTC (pyrrolidine dithiocarbamate), and a Ca2+ chelator, BAPTA-AM [1,2-bis(aminophenoxy)ethane N,N,N,N-tetraacetic acid tetra(acetoxymethyl) ester], which suggests a role for both reactive oxygen species and Ca2+ signalling in the Nrf2-activation process. By using inhibitors of cellular kinases, we showed further that HCV-mediated phosphorylation/activation of Nrf2 is mediated by the mitogen-activated protein (MAP) kinases p38 MAPK and janus kinase. We also observed enhanced phosphorylation of Akt and its downstream substrate Bad in HCV-infected cells. Furthermore, by using a small interfering RNA approach, our results suggest a potential role for HCV-mediated Nrf2 activation in the survival of HCV-infected cells, a condition favourable for liver oncogenesis, Taken together, these results provide an insight into the mechanisms by which HCV induces intracellular events relevant to chronic HCV infection.