Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection.

Carmine Mancone (1) , Claudia Montaldo (1, 2) , Laura Santangelo (2) , Cristina Di Giacomo (1) , Viviana Costa (1) , Laura Amicone (2) , Giuseppe Ippolito (1, 3) , Leopoldo Paolo Pucillo (1) , Tonino Alonzi (1) , Marco Tripodi (1, 2)

1 L. Spallanzani National Institute for Infectious Diseases
2 Department of Cellular Biotechnologies and Haematology
3 Department of epidemiology and pre-clinical research

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.

Domaines: Virologie; Biologie moléculaire

Carmine Mancone, Claudia Montaldo, Laura Santangelo, Cristina Di Giacomo, Viviana Costa, et al.. Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection.. Journal of Proteome Research, 2012, 11 (5), pp.2786-97. ⟨10.1021/pr201128s⟩. ⟨pasteur-00957464⟩