Iron regulates hepatitis C virus translation via stimulation of expression of translation initiation factor 3.
BACKGROUND
Although the response to treatment with interferon- alpha in individuals with chronic hepatitis C virus (HCV) infection is negatively associated with increased liver iron stores, the underlying mechanisms at work have remained elusive to date. The translation initiation factor 3 (eIF3) is essential for HCV translation, and thus the effects that iron perturbations have on eIF3 expression and HCV translation were studied here.


METHODS
eIF3 expression was analyzed by TaqMan polymerase chain reaction, Northern and Western blot analysis of HepG2 cells, and liver biopsies. Functional effects of iron on HCV mRNA translation were estimated by use of transient transfection experiments with bicistronic vectors.


RESULTS
Iron treatment of HepG2 cells increased eIF3 mRNA and protein expression, whereas iron chelation reduced it. Accordingly, iron-dependent stimulation of eIF3 specifically induced the expression of reporter genes under the control of regulatory HCV mRNA stem-loop structures. Moreover, a positive association between liver iron levels, eIF3 expression, and HCV expression was found when liver-biopsy samples from HCV-infected patients were analyzed.


CONCLUSIONS
Iron promotes the translation of HCV by stimulating the expression of eIF3, which may be one reason for the negative association between liver iron overload and HCV infection. Modulation of the affinity of eIF3 to bind to HCV mRNA may be a promising target for the treatment of chronic HCV infection.
Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria.
Igor
I
Theurl
Heinz
H
Zoller
Peter
P
Obrist
Christian
C
Datz
Felix
F
Bachmann
Richard M
RM
Elliott
Guenter
G
Weiss
D001706:Biopsy; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002712:Chlorides; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism*; D005290:Ferric Compounds / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000235:genetics
D002712:Chlorides; D039621:Eukaryotic Initiation Factor-3; D005290:Ferric Compounds; D012333:RNA, Messenger; D012367:RNA, Viral; C024555:ferric chloride