PKR 对 HCV1a 复制的调节作用依赖于 Huh7.5.1 细胞中 NF-κB 介导的干扰素β反应。
The modulation of hepatitis C virus 1a replication by PKR is dependent on NF-kB mediated interferon beta response in Huh7.5.1 cells.
机构信息
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Virology. 2013 Mar 30;438(1):28-36. doi: 10.1016/j.virol.2013.01.015. Epub 2013 Feb 9.
Abstract
Protein kinase R (PKR), a sensor of double-stranded RNA, plays an important role in the host response to viral infection. Hepatitis C genotype 2a virus (HCV2a) has been shown to induce PKR activation to suppress the translation of antiviral interferon stimulated genes (ISGs), suggesting that PKR inhibitor can be beneficial for treating chronically HCV-infected patients in conjunction with interferon alpha and ribavirin. However, in this study, we found that PKR inhibition using siRNA PKR, shRNA PKR or PKR inhibitor enhanced HCV 1a replication and rendered Huh7.5.1 cells more susceptible to HCV1a infection. Additionally, PKR silencing suppressed NF-kB activation and NF-kB mediated STAT1 phosphorylation in Huh7.5.1 cells and HCV1a persistently infected Huh7.5.1 cells (2HDD4). These effects were accompanied by a reduction of interferon beta response and thereby enhanced HCV1a replication in Huh7.5.1 cells. We conclude that host cells can employ PKR activation to restrict HCV1a replication through regulation of NF-kB expression.
摘要
蛋白激酶 R（PKR）是双链 RNA 的传感器，在宿主对病毒感染的反应中发挥重要作用。已经表明丙型肝炎病毒 2a 型（HCV2a）诱导 PKR 的激活，以抑制抗病毒干扰素刺激基因（ISGs）的翻译，这表明 PKR 抑制剂可以与干扰素 α 和利巴韦林联合用于治疗慢性 HCV 感染患者。然而，在这项研究中，我们发现使用 siRNA PKR、shRNA PKR 或 PKR 抑制剂抑制 PKR 会增强 HCV1a 的复制，并使 Huh7.5.1 细胞更容易感染 HCV1a。此外，PKR 沉默抑制了 Huh7.5.1 细胞和 HCV1a 持续感染 Huh7.5.1 细胞（2HDD4）中的 NF-κB 激活和 NF-κB 介导的 STAT1 磷酸化。这些效应伴随着干扰素β反应的减少，从而增强了 Huh7.5.1 细胞中的 HCV1a 复制。我们得出结论，宿主细胞可以通过调节 NF-κB 的表达来利用 PKR 的激活来限制 HCV1a 的复制。
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1
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Hepatology. 2012 Sep;56(3):831-40. doi: 10.1002/hep.25726. Epub 2012 Jul 26.
2
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Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10.
3
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J Virol. 2010 Nov;84(21):10991-8. doi: 10.1128/JVI.00900-10. Epub 2010 Sep 1.
4
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PLoS One. 2010 May 11;5(5):e10575. doi: 10.1371/journal.pone.0010575.
5
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J Mol Biol. 2010 Jul 16;400(3):393-412. doi: 10.1016/j.jmb.2010.04.059. Epub 2010 May 4.
6
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7
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8
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9
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