American Chemical Society
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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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posted on 2012-05-04, 00:00 authored by Carmine Mancone, Claudia Montaldo, Laura Santangelo, Cristina Di Giacomo, Viviana Costa, Laura Amicone, Giuseppe Ippolito, Leopoldo Paolo Pucillo, Tonino Alonzi, Marco Tripodi
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.