Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins
Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins
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DOI：
10.1128/jvi.02449-10
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发表时间：
2011-05-01
影响因子：
5.4
通讯作者：
Ray, Ranjit
中科院分区：
文献类型：
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作者：
Banerjee, Arup;Mazumdar, Budhaditya;Ray, Ranjit
人类补体的第四组分（C4）在先天免疫功能中起着重要作用。在慢性丙型肝炎病毒（HCV）感染患者中观察到C4活性显著降低，尽管其机制尚不清楚。在这项研究中，我们研究了丙型肝炎病毒的C4调节机制。慢性HCV感染患者的肝活检标本显示C4 mRNA水平显著低于非相关肝病患者的肝组织样本。此外，在用HCV基因型1a或2a的RNA转染的肝细胞中，两种亚型（C4 A和C4 B）的C4 mRNA水平显著降低。随后，观察到HCV核心或NS 5A对C4启动子活性的显著C4调节作用。HCV核心或NS 5A转基因小鼠显示C4 mRNA减少。γ干扰素（IFN-γ）诱导的C4启动子激活也受损的HCV蛋白的存在下。我们进一步证明，HCV核心减少了上游刺激因子1（USF-1）的表达，这是一种对基础C4表达很重要的转录因子。另一方面，表达HCV NS 5A的肝细胞抑制干扰素调节因子1（IRF-1）的表达，该因子对于IFN-γ诱导的C4表达是重要的。这些结果强调了HCV蛋白在建立慢性感染的先天免疫调节中的作用。
The fourth component of human complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with chronic hepatitis C virus (HCV) infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV infections displayed significantly lower C4 mRNA levels than liver tissue samples from patients with unrelated liver disease. Further, C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4 mRNA. Gamma interferon (IFN-gamma)-induced C4 promoter activation was also impaired in the presence of HCV proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a transcription factor important for basal C4 expression. On the other hand, the expression of interferon regulatory factor 1 (IRF-1), which is important for IFN-gamma-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV proteins in innate immune regulation in establishing a chronic infection.