Mechanism of hepatocyte injury via survival and death signaling induced by hepatitis viruses

在这项研究中，我们的目的是阐明肝细胞损伤的机制，通过诱导的存活和死亡信号的肝炎病毒。1)丙型肝炎病毒（HCV）核心蛋白通过肿瘤坏死因子受体相关因子激活NF-κ B依赖的信号通路。HCV核心蛋白的这种功能可能在HCV引起的炎症反应中起重要作用。事实上，HCV核心蛋白也通过NF-κB激活白细胞介素（IL）-8启动子。此外，HCV核心蛋白氨基酸序列的差异通过调节HCV感染患者中的IL-8诱导与肝炎活动相关。此外，HCV核心蛋白上调转化生长因子（TGF）β-1表达，提示HCV感染加重肝纤维化的新模式。2)HCV NS 3蛋白直接与TBK 1相互作用，这种结合导致TBK 1和IRF-3之间的结合受到抑制，IRF-3是产生干扰素-b的关键转录因子， 关于我们 导致IRF-3活化的抑制。这可能是NS 3蛋白抑制先天免疫应答和HCV感染持续存在的机制。3)HCV NS 4A和NS 4 B蛋白通过靶向翻译过程抑制细胞蛋白质合成。HCV NS 4A和NS 4 B蛋白具有翻译抑制作用。这种新的功能可能参与HCV感染并帮助其在宿主细胞中存活。4)HCV NS 5A蛋白在HCV感染过程中与p53和hTAFII 32相互作用并部分螯合p53和hTAFII 32，hTAFII 32是TFIID的组分和p53的必需共激活因子，并抑制p53介导的转录反式激活和细胞凋亡，这可能有助于HCV感染的肝癌发生。5)了解B型肝炎病毒（HBV）X蛋白（HBx）的功能是阐明HBV感染引起肝炎和肝癌发生机制的基础。我们通过亲和纯化和质谱的结合鉴定了热休克蛋白60（Hsp 60）作为HBx的新细胞靶点。激光共聚焦显微镜显示HBx和Hsp 60共定位于线粒体内。此外，TUNEL显示，HspGO引入细胞促进HBx诱导的细胞凋亡。这些发现表明分子伴侣蛋白Hsp 60对HBV病毒蛋白功能的重要性。6)丁型肝炎病毒（HDV）是HBV的天然卫星病毒。HBx单独或与HDV抗原的大同种型（LHDAg）协同激活血清反应元件（SRE）依赖性途径。HBx激活Elk-1的转录能力，而LHDAg激活血清反应因子（SRF）的转录能力。因此，HBx和LHDAg协同激活SRE依赖性途径。这些结果可能有助于我们了解HBV和HDV合并感染患者的临床现象。少

In this study, we aimed to clarify the mechanism of hepatocyte injury via survival and death signaling induced by hepatitis viruses. 1)Hepatitis C virus(HCV) core protein activated NF-κB-dependent signaling pathway through tumor necrosis factor receptor-associated factor. This function of HCV core protein may play an important role in the inflammatory reaction induced by this virus. In fact, HCV core protein activated also interteukin(IL)-8 promoter through NF-κB. Moreover, differences in the amino acid sequence of HCV core protein correlates with hepatitis activity through modulation of IL-8 induction in HCV infected patients. In addition, HCV core protein upregulated transforming growth factor(TGF)β-1 expression, suggesting a new paradigm for exacerbation of liver fibrosis by HCV infection. 2)HCV NS3 protein interacts directly with TBK1,and that this binding results in the inhibition of the association between TBK1 and IRF-3,a key transcriptional factor to produce interferon-b, which … More leads to the inhibition of IRF-3 activation. This might show the mechanisms in the inhbition of innate immune responses and in the persistence of HCV infection by NS3 protein. 3)HCV NS4A and NS4B proteins inhibited cellular protein synthesis by targeting the process of translation. HCV NS4A and NS4B proteins have an effect of translational inhbition. This novel function may be involved in HCV infection and help its survival in host cells. 4)HCV NS5A protein interacts with and partially sequestrates p53 and hTAFII32,a component of TFIID and an essential coactivator of p53, in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection. 5)Uncerstanding the function of hepatitis B virus(HBV) X protein(HBx) is fundamental to elucidating the underlying mechanisms of hepatitis and hepatocarcinogenesis caused by HBV infection. We identified heat shock protein 60(Hsp60) as a novel cellular target of HBx by the combination of affinity purification and mass spectrometry. Confocal laser microscopy demonstrated that HBx and Hsp60 colocalized in mitochondria. Furthermore, TUNEL revealed that the introduction of HspGO into cells facilitated HBx-induced apoptosis. These findings suggest the importance of the molecular chaperon protein Hsp60 to the function of HBV viral proteins. 6)Hepatitis delta virus(HDV) is a naturally occurring satellite of HBV. HBx, alone or with the large isoform of HDV antigens(LHDAg), synergistically activated the serum response element(SRE)-dependent pathway. HBx activated the transcriptional ability of Elk-1,whereas LHDAg activated the transcritional ability of serum response factor(SRF). Thus, HBx and LHDAg synergistically activated the SRE-dependent pathway. These results may help us understand clinical phenomena in patients coinfected with HBV and HDV. Less