Key result
Disruption of the eIF4G-PABP interaction abolished or severely reduced poly(A) tail-mediated stimulation of picornavirus IRES-driven translation, whereas HCV IRES translation was stimulated by its 3' X region independently of this interaction.
The eIF4G-PABP interaction is required for poly(A) tail-mediated stimulation of picornavirus IRES-driven translation, highlighting conserved mRNA 5'-3' cross-talk mechanisms.
Does not support clinical translation; extends models of distinct 3'-end dependencies in picornavirus versus HCV IRES translation.
Efficient translation of most eukaryotic mRNAs results from synergistic cooperation between the 5' m(7)GpppN cap and the 3' poly(A) tail. In contrast to such mRNAs, the polyadenylated genomic RNAs of picornaviruses are not capped, and translation is initiated internally, driven by an extensive sequence termed IRES (for internal ribosome entry segment). Here we have used our recently described poly(A)-dependent rabbit reticulocyte lysate cell-free translation system to study the role of mRNA polyadenylation in IRES-driven translation. Polyadenylation significantly stimulated translation driven by representatives of each of the three types of picornaviral IRES (poliovirus, encephalomyocarditis virus, and hepatitis A virus, respectively). This did not result from a poly(A)-dependent alteration of mRNA stability in our in vitro translation system but was very sensitive to salt concentration. Disruption of the eukaryotic initiation factor 4G-poly(A) binding protein (eIF4G-PABP) interaction or cleavage of eIF4G abolished or severely reduced poly(A) tail-mediated stimulation of picornavirus IRES-driven translation. In contrast, translation driven by the flaviviral hepatitis C virus (HCV) IRES was not stimulated by polyadenylation but rather by the authentic viral RNA 3' end: the highly structured X region. X region-mediated stimulation of HCV IRES activity was not affected by disruption of the eIF4G-PABP interaction. These data demonstrate that the protein-protein interactions required for synergistic cooperativity on capped and polyadenylated cellular mRNAs mediate 3'-end stimulation of picornaviral IRES activity but not HCV IRES activity. Their implications for the picornavirus infectious cycle and for the increasing number of identified cellular IRES-carrying mRNAs are discussed.
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Michel et al. (2001) studied Picornavirus and Hepatitis C Virus translation mechanisms. Polyadenylation and eIF4G-PABP interaction disruption vs. Non-polyadenylated RNA and intact eIF4G-PABP interaction was evaluated on IRES-driven translation efficiency. Disruption of the eIF4G-PABP interaction abolished or severely reduced poly(A) tail-mediated stimulation of picornavirus IRES-driven translation, whereas HCV IRES translation was stimulated by its 3' X region independently of this interaction.
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