Abstract
Internal ribosome entry sites (IRESs) are important RNA-based translation initiation signals, critical for infection by many pathogenic viruses. The hepatitis C virus (HCV) IRES is the prototype for the type 3 IRESs and is also invaluable for exploring principles of eukaryotic translation initiation, in general. Current mechanistic models for the type 3 IRESs are useful but they also present paradoxes, including how they can function both with and without eukaryotic initiation factor (eIF) 2. We discovered that eIF1A is necessary for efficient activity where it stabilizes tRNA binding and inspects the codon-anticodon interaction, especially important in the IRES' eIF2-independent mode. These data support a model in which the IRES binds preassembled translation preinitiation complexes and remodels them to generate eukaryotic initiation complexes with bacterial-like features. This model explains previous data, reconciles eIF2-dependent and -independent pathways, and illustrates how RNA structure-based control can respond to changing cellular conditions.
Highlights
Translation initiation requires a messenger RNA placed in the small ribosomal subunit’s decoding groove with the correct start codon paired to the anticodon of a charged initiator methionine tRNA (Met-tRNAiMet)
Translation preinitiation complexes assembled on the hepatitis C virus (HCV) Internal ribosome entry sites (IRESs) contain eIF1A
We examined the effect of mutating important HCV IRES subdomains on factor binding (Figure 1B–D)
Summary
Translation initiation requires a messenger RNA (mRNA) placed in the small ribosomal subunit’s decoding groove with the correct start codon paired to the anticodon of a charged initiator methionine tRNA (Met-tRNAiMet). The canonical process to accomplish this requires >12 eukaryotic translation initiation factor (eIF) proteins (Jackson et al, 2010). Translation initiation in eukaryotes can occur by internal ribosome entry site (IRES) RNAs (Jackson, 2005). IRESs of viral origin use a subset or none of the eIFs and some bind directly to the ribosome (Filbin and Kieft, 2009; Thompson, 2012), positioning the start codon without a 5’ cap or scanning. IRESs are important in viral infection and are key players in regulation of gene expression, but the full repertoire of strategies they use is not completely understood
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