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

TL;DR

This study reveals how the RNA helicase DDX5 inhibits foot-and-mouth disease virus replication by blocking translation and RNA synthesis, but is counteracted by a viral protein.

Contribution

DDX5 is identified as a novel IRES trans-acting factor that inhibits FMDV translation and RNA replication through two distinct mechanisms.

Findings

DDX5 binds to the IRES D4 domain and suppresses FMDV translation by blocking ribosome assembly.

DDX5 interacts with viral RNA polymerase and 3′UTR to disrupt RNA synthesis.

Viral protein 3ABCD counteracts DDX5 by cleaving it, restoring viral replication.

Abstract

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.

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 Picornaviridae 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.

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