RNA helicase DDX5 regulates the translation and genomic replication of foot-and-mouth disease virus

作者：Wu J, Abdullah SW, Li P, Wang X, Ren M, Huang Y, Guo X, Sun S, Guo H · 发表于：Journal of virology · 年份：2026 · DOI：10.1128/jvi.01731-25

UNLABELLED: The internal ribosome entry site (IRES) is a cis-acting structural element found in many viral mRNAs, which mediates cap-independent translation by recruiting various RNA-binding proteins and IRES trans-acting factors (ITAFs). Foot-and-mouth disease virus (FMDV), a significant member of the Picornaviridae family, contains a functional IRES element that contributes to viral protein translation and RNA synthesis. Here, we uncover a previously unrecognized mechanism in which DEAD-box RNA helicase 5 (DDX5) functions as a novel ITAF, inhibiting FMDV translation and viral RNA synthesis through two distinct strategies. First, DDX5 binds to the D4 domain of the IRES, suppressing FMDV IRES-driven translation by blocking the assembly of 80S ribosome. Second, DDX5 interacts with the viral RNA-dependent RNA polymerase 3Dpol and 3'UTR of FMDV, disrupting viral RNA synthesis. Conversely, the inhibitory effect of DDX5 was counteracted by viral precursor protein 3ABCD-mediated proteolysis of 3Cpro. Furthermore, the functional importance of DDX5 in FMDV pathogenicity was further validated in vivo experiments. These findings enhance our understanding of how viruses exploit or antagonize cellular factors to regulate IRES-driven translation and provide new insights into translational control during viral infection. IMPORTANCE: Picornaviruses have evolved various strategies to compete and dominate host protein synthesis machinery, often bypassing cap-dependent mRNA translation. Foot-...