Comparison between the HCV IRES domain IV RNA structure and the Iron Responsive Element

Ebenezer Tumban,William B Lott,Jenna M Painter

doi:10.1186/1477-5751-8-4

Abstract

BackgroundSerum ferritin and hepatic iron concentrations are frequently elevated in patients who are chronically infected with the hepatitis C virus (HCV), and hepatic iron concentration has been used to predict response to interferon therapy, but these correlations are not well understood. The HCV genome contains an RNA structure resembling an iron responsive element (IRE) in its internal ribosome entry site (IRES) structural domain IV (dIV). An IRE is a stem loop structure used to control the expression of eukaryotic proteins involved in iron homeostasis by either inhibiting ribosomal binding or protecting the mRNA from nuclease degradation. The HCV structure, located within the binding site of the 40S ribosomal subunit, might function as an authentic IRE or by an IRE-like mechanism.ResultsElectrophoretic mobility shift assays showed that the HCV IRES domain IV structure does not interact with the iron regulatory protein 1 (IRP1) in vitro. Systematic HCV IRES RNA mutagenesis suggested that IRP1 cannot accommodate the shape of the wild type HCV IRES dIV RNA structure.ConclusionThe HCV IRES dIV RNA structure is not an authentic IRE. The possibility that this RNA structure is responsible for the observed correlations between intracellular iron concentration and HCV infection parameters through an IRE-like mechanism in response to some other cellular signal remains to be tested.

Highlights

Serum ferritin and hepatic iron concentrations are frequently elevated in patients who are chronically infected with the hepatitis C virus (HCV), and hepatic iron concentration has been used to predict response to interferon therapy, but these correlations are not well understood
An RNA structural element located at the junction between the open reading frame (ORF) and the 5' untranslated region (UTR) of the HCV genome bears striking structural and sequential similarities to the iron responsive element (IRE), an RNA structure found in some eukaryotic mRNA that controls gene expression in response to intracellular iron concentration [9]
RNA binding to Human IRP1 (hIRP1) Since the HCV internal ribosome entry site (IRES) domain IV (dIV) structure differs from the consensus IRE at only three characteristics, a mutant RNA panel was constructed to evaluate the relative binding contribution of each characteristic

Summary

Introduction

Serum ferritin and hepatic iron concentrations are frequently elevated in patients who are chronically infected with the hepatitis C virus (HCV), and hepatic iron concentration has been used to predict response to interferon therapy, but these correlations are not well understood. An RNA structural element located at the junction between the open reading frame (ORF) and the 5' untranslated region (UTR) of the HCV genome bears striking structural and sequential similarities to the iron responsive element (IRE), an RNA structure found in some eukaryotic mRNA that controls gene expression in response to intracellular iron concentration [9]. If this HCV RNA element functions as an authentic IRE, iron depletion in an HCV infected cell would be expected to inhibit viral protein expression and could potentially decrease subsequent viral replication. A possible relationship between this HCV RNA structure and the IRE was investigated

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Discussion

Conclusion