Tumban Ebenezer, Painter Jenna M, Lott William B
Molecular Biology Program, New Mexico State University, Las Cruces, NM 88003-8001, USA.
J Negat Results Biomed. 2009 Feb 18;8:4. doi: 10.1186/1477-5751-8-4.
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. 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.
Electrophoretic 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.
The 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.
丙型肝炎病毒(HCV)慢性感染患者的血清铁蛋白和肝脏铁浓度经常升高,肝脏铁浓度已被用于预测对干扰素治疗的反应,但这些相关性尚未完全明确。HCV基因组在其内部核糖体进入位点(IRES)结构域IV(dIV)中含有一个类似于铁反应元件(IRE)的RNA结构。IRE是一种茎环结构,通过抑制核糖体结合或保护mRNA免受核酸酶降解来控制参与铁稳态的真核蛋白的表达。位于40S核糖体亚基结合位点内的HCV结构可能作为一个真正的IRE发挥作用,或通过类似IRE的机制发挥作用。
电泳迁移率变动分析表明,HCV IRES结构域IV结构在体外不与铁调节蛋白1(IRP1)相互作用。系统性的HCV IRES RNA诱变表明,IRP1无法适应野生型HCV IRES dIV RNA结构的形状。
HCV IRES dIV RNA结构不是一个真正的IRE。这种RNA结构是否通过类似IRE的机制对某些其他细胞信号作出反应,从而导致细胞内铁浓度与HCV感染参数之间观察到的相关性,仍有待验证。