Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 17, Issue 11, Pages 4632-4644Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E06-06-0478
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Funding
- NCI NIH HHS [R01 CA114475, CA-114475] Funding Source: Medline
- NIGMS NIH HHS [R01 GM062128, GM-26796, GM-62128, R01 GM026796] Funding Source: Medline
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A cornerstone of the antiviral interferon response is phosphorylation of eukaryotic initiation factor (eIf)2 alpha. This limits the availability of eIF2.GTP.Met-tRNA(i)(Met) 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 eIF2 alpha and Met-tRNA(i)(Met) are present, defining a tactic used by HCV to evade part of the antiviral interferon response.
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