Iron Inactivates the RNA Polymerase NS5B and Suppresses Subgenomic Replication of Hepatitis C Virus

Clinical data suggest that iron is a negative factor in chronic hepatitis C; however, the molecular mechanisms by which iron modulates the infectious cycle of hepatitis C virus (HCV) remain elusive. To explore this, we utilized cells expressing a HCV replicon as a well-established model for viral re...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-03, Vol.280 (10), p.9049-9057
Main Authors: Fillebeen, Carine, Rivas-Estilla, Ana Maria, Bisaillon, Martin, Ponka, Prem, Muckenthaler, Martina, Hentze, Matthias W., Koromilas, Antonis E., Pantopoulos, Kostas
Format: Article
Language:English
Subjects:
Carcinoma, Hepatocellular
Cell Line, Tumor
Hepacivirus - drug effects
Hepacivirus - genetics
Hepacivirus - physiology
Hepatitis C virus
Humans
Iron - pharmacology
Kinetics
Liver Neoplasms
Protein Binding
Recombinant Fusion Proteins - metabolism
Replicon - drug effects
RNA-Dependent RNA Polymerase - antagonists & inhibitors
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - metabolism
Virus Replication - drug effects
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Summary:Clinical data suggest that iron is a negative factor in chronic hepatitis C; however, the molecular mechanisms by which iron modulates the infectious cycle of hepatitis C virus (HCV) remain elusive. To explore this, we utilized cells expressing a HCV replicon as a well-established model for viral replication. We demonstrate that iron administration dramatically inhibits the expression of viral proteins and RNA, without significantly affecting its translation or stability. Experiments with purified recombinant HCV RNA polymerase (NS5B) revealed that iron binds specifically and with high affinity (apparent Kd: 6 and 60 μm for Fe2+ and Fe3+, respectively) to the protein's Mg2+-binding pocket, thereby inhibiting its enzymatic activity. We propose that iron impairs HCV replication by inactivating NS5B and that its negative effects in chronic hepatitis C may be primarily due to attenuation of antiviral immune responses. Our data provide a direct molecular link between iron and HCV replication.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M412687200