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

Picornaviruses have evolved various strategies to compete and dominate host protein synthesis machinery, often bypassing cap-dependent mRNA translation. Foot-and-mouth disease virus (FMDV), a highly contagious member of the <i>Picornaviridae</i> family, is a globally significant pathogen responsible for severe epidemics in cloven-hoofed animals, posing substantial economic and agricultural threats. In this study, we identified DEAD-box RNA helicase 5 (DDX5) as a novel IRES trans-acting factor that plays a critical role in the translational regulation of FMDV. Specifically, DDX5 was found to negatively modulate FMDV IRES-driven translation and suppress viral RNA replication during infection. Furthermore, we elucidated a novel viral counteraction mechanism in which DDX5 is cleaved by the viral precursor molecule 3ABCD through proteolytic activity. These findings provide new insights into the complex interplay between viral and host factors, advancing our understanding of translational control during picornavirus infection and offering potential avenues for the development of antiviral strategies.