Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus

被引:92
作者
Fillebeen, C
Rivas-Estilla, AM
Bisaillon, M
Ponka, P
Muckenthaler, M
Hentze, MW
Koromilas, AE
Pantopoulos, K
机构
[1] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
[2] Univ Sherbrooke, Fac Med, Dept Biochim, Sherbrooke, PQ J1H 5N4, Canada
[3] European Mol Biol Lab, D-69117 Heidelberg, Germany
[4] McGill Univ, Fac Med, Montreal, PQ H3G 1Y6, Canada
关键词
D O I
10.1074/jbc.M412687200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 K-d: 6 and 60 muM 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.
引用
收藏
页码:9049 / 9057
页数:9
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