Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus
Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus
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DOI：
10.1002/hep.22176
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发表时间：
2008-04-01
期刊：
影响因子：
13.5
通讯作者：
Omata, Masao
中科院分区：
文献类型：
--
作者：
Dharel, Narayan;Kato, Naoya;Omata, Masao
丙型肝炎病毒（HCV）感染通常会导致慢性肝炎，最终导致肝硬化和肝细胞癌。 1 型干扰素 (IFN-α/β) 构成针对病毒感染（包括 HCV）的主要细胞防御。 IFN 与其受体结合会激活相关的 Jak1 和 Tyk2 激酶，最终导致信号转导器和转录蛋白 (STAT)1-STAT2-干扰素调节因子 (IRF)9 激活剂的磷酸化和组装，称为干扰素刺激基因因子 3，该复合物易位到细胞核中并与干扰素刺激反应元件 (ISRE) 结合，从而导致 多种抗病毒基因的转录诱导，包括双链 RNA 激活蛋白激酶 (PKR)、2',5'-寡腺苷酸合成酶 (OAS) 和粘病毒抗性蛋白 A (MxA)。了解病毒如何逃避这种细胞先天防御并建立慢性感染的机制是开发更好的 HCV 感染治疗方法的关键。在这里，我们证明 p53 在细胞对 HCV 的先天防御中发挥着至关重要的作用。当 Huh7 细胞的 p53 表达被抑制时，我们观察到 HCV RNA 复制和病毒蛋白表达水平显着升高。此外，IFN 治疗在抑制 p53 敲低 (p53kd) 的 HCV RNA 复制方面效果较差，嗯？细胞。事实上，p53kd 中 ISRE 的激活和 ISG 的诱导显着减弱？细胞和p53被发现直接与IRF9相互作用。结论：这些观察结果强调了肿瘤抑制因子 p53 在针对 HCV 的细胞抗病毒免疫中的潜在贡献，并具有可能的治疗意义。
Infection by hepatitis C virus (HCV) usually results into chronic hepatitis that can ultimately lead to cirrhosis and hepatocellular carcinoma. Type 1 interferons (IFN-alpha/beta) constitute the primary cellular defense against viral infection including HCV. IFN binding to their receptors activates associated Jak1 and Tyk2 kinases, which ultimately leads to phosphorylation and assembly of a signal transducer and activator of transcription protein (STAT)1-STAT2-interferon regulatory factor (IRF)9 trimetric complex called interferon-stimulated gene factor 3 that translocates into the nucleus and binds to the interferon-stimulated response elements (ISRE), leading to transcriptional induction of several antiviral genes, including double-stranded RNA-activated protein kinase (PKR), 2',5'-oligoadenylate synthetase (OAS), and myxovirus resistance protein A (MxA). Understanding the mechanisms of how the virus evades this cellular innate defense and establishes a chronic infection is the key for the development of better therapeutics against HCV infection. Here, we demonstrate that p53 could have a crucial role in the cellular innate defense against HCV. We observed significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells when their p53 expressions were knocked down. Moreover, IFN treatment was less effective in inhibiting the HCV RNA replication in the p53-knocked-down (p53kd) Huh? cells. In fact, the activation of the ISRE and the induction of ISGs were significantly attenuated in the p53kd Huh? cells and p53 was found to directly interact with IRF9. Conclusion: These observations underscore the potential contributions of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implications.