Hepatitis C virus core protein down-regulates transcription of interferon-induced antiviral genes
Hepatitis C virus core protein down-regulates transcription of interferon-induced antiviral genes
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DOI：
10.1086/426509
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发表时间：
2005-01-01
影响因子：
6.4
通讯作者：
Carreño, V
中科院分区：
文献类型：
--
作者：
de Lucas, S;Bartolomé, J;Carreño, V
背景。丙型肝炎病毒（HCV）蛋白干扰干扰素(IFN)- α诱导的Jak/信号转导和转录激活因子（STAT）途径。哪种蛋白质对这种影响负责，以及这种干扰是否导致ifn诱导基因的下调仍然存在争议。我们分析了HCV核心（HCV- co）蛋白对ifn诱导的抗病毒基因表达的影响。用质粒pHCV-Co转染HepG2细胞，经ifn - α处理后，检测MxA、蛋白激酶R （PKR）和2‘-5’寡聚腺苷酸合成酶（2'-5' oas） mRNA的水平。对pHCV-Co和pMx4CAT（含MxA基因启动子）共转染并经IFN处理的细胞进行Chloramphenycol acethyl transferase （CAT）分析。采用电泳迁移率转移法，Western-blot分析STAT 1和STAT 2。通过下调MxA基因启动子，phcv共转染细胞中MxA mRNA水平呈剂量依赖性下降。HCV-Co蛋白抑制ifn刺激基因因子3 （ISGF3）与ifn刺激反应元件（ISRE）的结合。细胞内STAT 1和2的分布在IFN治疗后没有改变。HCV-Co蛋白的表达也导致PKR和2′-5′oas基因的表达下调。HCV-Co蛋白通过降低ISGF3与ISRE的结合抑制ifn - α诱导的抗病毒基因转录。
Background. Hepatitis C virus (HCV) proteins interfere with the interferon (IFN)-alpha-induced Jak/signal transducer and activator of transcription ( STAT) pathway. Which protein is responsible for this effect and whether this interference results in down-regulation of IFN-induced genes remain controversial. We analyzed the effect of HCV core (HCV-Co) protein on expression of IFN-induced antiviral genes.Methods. HepG2 cells were transfected with the plasmid pHCV-Co, and, after treatment with IFN-alpha, levels of MxA, protein kinase R (PKR), and 2'-5' oligoadenylate synthetase (2'-5'OAS) mRNA were determined. Chloramphenycol acethyl transferase (CAT) analysis was performed on cells cotransfected with pHCV-Co and pMx4CAT ( containing the MxA gene promoter) and treated with IFN. Electrophoretic mobility shift assays were used, and Western-blot analysis of STAT 1 and 2 was performed.Results. Levels of MxA mRNA in pHCV-Co-transfected cells decreased in a dose-dependent manner, by down-regulation of the MxA gene promoter. HCV-Co protein inhibits binding of IFN-stimulated gene factor 3 (ISGF3) to the IFN-stimulated response element (ISRE). Intracellular distribution of STAT 1 and 2 was not modified after treatment with IFN. Expression of HCV-Co protein also results in down-regulation of expression of PKR and 2'-5'OAS genes.Conclusion. HCV-Co protein inhibits IFN-alpha-induced transcription of antiviral genes by decreasing binding of ISGF3 to the ISRE.