The 3' End of the Foot-and-mouth Disease Virus Genome Establishes Two Distinct Long-range RNA-RNA Interactions with the 5' End Region

The untranslated regions (UTRs) of the foot-and-mouth disease virus (FMDV) genome contain multiple functional elements. In the 5' UTR, the internal ribosome entry site (IRES) element governs cap-independent translation initiation, whereas the S region is presumably involved in RNA replication. The 3' UTR, composed of two stem-loops and a poly(A) tract, is required for viral infectivity and stimulates IRES activity. Here, it was found that the 3' end established two distinct strand-specific, long-range RNA-RNA interactions, one with the S region and another with the IRES element. These interactions were not observed with the 3' UTR of a different picornavirus. Several results indicated that different 3' UTR motifs participated in IRES or S region interactions. Firstly, a high-order structure adopted by both the entire IRES and the 3' UTR was essential for RNA interaction. In contrast, the S region interacted with each of the stem-loops. Secondly, S-3' UTR interaction but not IRES-3' UTR interaction was dependent on a poly(A)-dependent conformation. However, no other complexes were observed in mixtures containing the three transcripts, suggesting that these regions did not interact simultaneously with the 3' UTR probe. Cellular proteins have been found to bind the S region and one of these also binds to the 3' UTR in a competitive manner. Our data suggest that 5'-3'-end bridging through both direct RNA-RNA contacts and RNA-protein interactions may play an essential role in the FMDV replication cycle.