Functional interaction of translation initiation factor elF4G with the foot-and-mouth disease virus internal ribosome entry site

In the life-cycle of picornaviruses, the synthesis of the viral polyprotein is initiated cap-independently at the internal ribosome entry site (IRES) far downstream from the 5' end of the viral plus-strand RNA. The cis-acting IRES RNA elements serve as binding sites for translation initiation factor s that guide the ribosomes to an internal site of the viral RNA. In this st udy, we show that the eukaryotic translation initiation factor elF4G intera cts directly with the IRES of foot-and-mouth disease virus (FMDV). elF4G bi nds mainly to the large Y-shaped stem-loop 4 RNA structure in the 3' region of the FMDV IRES element, whereas stem-loop 5 contributes only slightly to elF4G binding. Two subdomains of stem-loop 4 are absolutely essential for elF4G binding, whereas another subdomain contributes to a lesser extent to binding of elF4G. At the functional level, the translational activity of st em-loop 4 subdomain mutants correlates with the efficiency of binding of el F4G in the UV cross-link assay. This indicates that the interaction of elF4 G with the IRES is crucial for the initiation of FMDV translation. A model for the interaction of initiation factors with the IRES element is discusse d.