Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2 · GTP · Met-tRNAiMet ternary complex availability

Francis Robert, Lee D. Kapp, Shakila N. Khan, Michael G. Acker, Sarah Kolitz, Shirin Kazemi, Randal J. Kaufman, William C. Merrick, Antonis E. Koromilas, Jon R. Lorsch, Jerry Pelletier

Research output: Contribution to journalArticlepeer-review

Abstract

A cornerstone of the antiviral interferon response is phosphorylation of eukaryotic initiation factor (eIF)2α. This limits the availability of eIF2-GTP-Met-tRNAiMet ternary complexes, reduces formation of 43S preinitiation complexes, and blocks viral (and most cellular) mRNA translation. However, many viruses have developed counterstrategies that circumvent this cellular response. Herein, we characterize a novel class of translation initiation inhibitors that block ternary complex formation and prevent the assembly of 43S preinitiation complexes. We find that translation driven by the HCV IRES is refractory to inhibition by these compounds at concentrations that effectively block cap-dependent translation in vitro and in vivo. Analysis of initiation complexes formed on the HCV IRES in the presence of inhibitor indicates that eIF2α and Met-tRNAiMet are present, defining a tactic used by HCV to evade part of the antiviral interferon response.

Original languageEnglish (US)
Pages (from-to)4632-4644
Number of pages13
JournalMolecular biology of the cell
Volume17
Issue number11
DOIs
StatePublished - Nov 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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