Iron increases translation initiation directed by internal ribosome entry site of hepatitis C virus.
Although increased liver iron in individuals with chronic hepatitis C virus (HCV) is associated with a poor response to interferon therapy, the underlying molecular mechanisms are poorly understood. In this study, we show that iron enhances the translation initiation mediated by the internal ribosome entry site (IRES) of HCV. We also demonstrate by UV cross-linking analysis that specific cellular proteins bind to HCV 5' untranslated region (5' UTR) in an iron-dependent manner. Notably, p85 and p110 are competed out for their binding to HCV 5' UTR when excess amounts of iron-responsive element (IRE) competitor RNAs are treated. This indicates that at least these two factors are common proteins for binding to HCV 5' UTR and IRE. Our results, taken together, suggest that intracellular iron modulates the iron sensing pathway and HCV IRES-dependent translation by changing the binding affinities of the common cellular factors to IRE and HCV IRES, respectively. As a consequence, the coordinated regulation of gene expression by intracellular iron could provide favorable conditions for HCV proliferation.
Cho
Hana
H
School of Life Sciences and Biotechnology, Korea University, Seoul, 136-701, Republic of Korea.
Lee
Hyung Chul
HC
Jang
Sung Key
SK
Kim
Yoon Ki
YK
D020121:5' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational; D011485:Protein Binding; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*
D020121:5' Untranslated Regions; D035925:Iron-Regulatory Proteins; D012367:RNA, Viral; D007501:Iron