Hepatitis C Virus Impairs the Induction of Cytoprotective Nrf2 Target Genes by Delocalization of Small Maf Proteins
Hepatitis C Virus Impairs the Induction of Cytoprotective Nrf2 Target Genes by Delocalization of Small Maf Proteins
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DOI：
10.1074/jbc.m110.186684
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发表时间：
2011-03-18
影响因子：
4.8
通讯作者：
Hildt, Eberhard
中科院分区：
文献类型：
--
作者：
Carvajal-Yepes, Monica;Himmelsbach, Kiyoshi;Hildt, Eberhard
多种细胞保护基因的表达受其启动子中的短顺式作用元件（称为抗氧化反应元件（战神））调节。ARE介导的基因表达的中心调节因子是NF-E2相关因子2（Nrf 2）。Nrf 2/ARE调控基因对维持细胞完整性至关重要。丙型肝炎病毒抑制ARE调节基因的诱导，但ARE调节基因表达的诱导或抑制均不直接影响HCV复制。在HCV复制细胞中，核心蛋白触发sMaf蛋白从细胞核到复制子复合物的离域。这里sMafs绑定到NS 3。胞核sMaf蛋白阻止Nrf 2进入细胞核，从而抑制Nrf 2/ARE调控基因的诱导。这导致细胞保护基因的表达降低。与这一发现相一致，ROI的消除在HCV复制细胞中受损，如通过升高的蛋白质氧化或8-OH-dG形成所证明的，反映了DNA损伤。总之，这些数据确定了一种新的Nrf 2调控机制，并表明Nrf 2/ARE调控基因的HCV依赖性抑制通过提高细胞内ROI（影响宿主基因组的完整性和再生过程）赋予HCV相关的发病机制。
The expression of a variety of cytoprotective genes is regulated by short cis-acting elements in their promoters, called antioxidant response elements (AREs). A central regulator of ARE-mediated gene expression is the NF-E2-related factor 2 (Nrf2). Nrf2/ARE-regulated genes are crucial for the maintenance of cellular integrity. Hepatitis C virus inhibits the induction of ARE-regulated genes, but neither induction nor inhibition of ARE-regulated gene expression affects HCV replication directly. In HCV-replicating cells the core protein triggers the delocalization of sMaf proteins from the nucleus to the replicon complex. Here sMafs bind to NS3. The extranuclear sMaf proteins prevent Nrf2 from entry in the nucleus and thereby inhibit the induction of Nrf2/ARE-regulated genes. This results in the decreased expression of cytoprotective genes. Consistent with this finding, the elimination of ROI is impaired in HCV-replicating cells as demonstrated by elevated protein oxidation or 8-OH-dG formation, reflecting DNA damage. In conclusion, these data identified a novel mechanism of Nrf2 regulation and suggest that the HCV-dependent inhibition of Nrf2/ARE-regulated genes confers to the HCV-associated pathogenesis by elevation of intracellular ROI that affect integrity of the host genome and regenerative processes.