Ferritin Heavy Chain Is the Host Factor Responsible for HCV-Induced Inhibition of apoB-100 Production and Is Required for Efficient Viral Infection
Ferritin Heavy Chain Is the Host Factor Responsible for HCV-Induced Inhibition of apoB-100 Production and Is Required for Efficient Viral Infection
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DOI：
10.1021/pr201128s
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发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Tripodi, Marco
中科院分区：
文献类型：
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作者：
Mancone, Carmine;Montaldo, Claudia;Tripodi, Marco
肝脏脂肪输出是通过含有载脂蛋白B-100的脂蛋白的产生而发生的，而脂蛋白的产生受损则会导致肝脏脂肪变性。丙型肝炎病毒感染与载脂蛋白B-100分泌失调和脂肪变性有关；然而，丙型肝炎病毒影响载脂蛋白B-100分泌的分子机制尚不清楚。在这里，结合定量蛋白质组学和计算生物学，我们提出铁蛋白重链(FTH)是apoB-100产生抑制的细胞决定因素。通过分子分析，我们发现丙型肝炎病毒非结构蛋白和NS5A似乎足以诱导FTH上调。FTH反过来又被发现抑制apoB-100的分泌，导致通过蛋白酶体增加细胞内的降解。值得注意的是，siRNA下调细胞内FTH可恢复apoB-100的分泌。在JFH-1丙型肝炎病毒细胞培养系统(HCVcc)和丙型肝炎病毒感染者中，铁蛋白与血浆apoB-100浓度也呈负相关。最后，我们发现FTH的表达是强健的丙型肝炎病毒感染所必需的。这些观察为肝脏脂肪变性的发生提供了进一步的分子解释，并允许对新的治疗和抗病毒策略进行假设。
Hepatic fat export occurs by apolipoprotein B-100-containing lipoprotein production, whereas impaired production leads to liver steatosis. Hepatitis C virus (HCV) infection is associated to dysregulation of apoB-100 secretion and steatosis; however, the molecular mechanism by which HCV affects the apoB-100 secretion is not understood. Here, combining quantitative proteomics and computational biology, we propose ferritin heavy chain (Fth) as being the cellular determinant of apoB-100 production inhibition. By means of molecular analyses, we found that HCV nonstructural proteins and NS5A appear to be sufficient for inducing Fth up-regulation. Fth in turn was found to inhibit apoB-100 secretion leading to increased intracellular degradation via proteasome. Notably, intracellular Fth down-regulation by siRNA restores apoB-100 secretion. The inverse correlation between ferritin and plasma apoB-100 concentrations was also found in JFH-1 HCV cell culture systems (HCVcc) and HCV-infected patients. Finally, Fth expression was found to be required for robust HCV infection. These observations provide a further molecular explanation for the onset of liver steatosis and allow for hypothesizing on new therapeutic and antiviral strategies.