Foot‐and‐mouth disease virus 2B protein antagonizes STING‐induced antiviral activity by targeting YTHDF2

Abstract Foot‐and‐mouth disease virus (FMDV) infection modulates the retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs) pathways to inhibit the innate immune responses in the host. However, the mechanism by which FMDV antagonizes the DNA‐induced signaling pathway remains to be clarified. In this study, we determined that FMDV infection inhibited stimulator of interferon genes (STING) at the levels of both mRNA and protein expression, and FMDV 2B and 3C pro proteins promoted STING decline. FMDV 3C pro induced the decrease in STING depending on its protease activity. FMDV 2B reduced STING expression by disrupting its mRNA level. Mechanistically, 2B inhibited the mRNA of STING by recruiting YTH m6A RNA‐binding protein 2 (YTHDF2) to bind to STING mRNA, repressing the generation of FMDV‐induced type‐I interferon and facilitating virus replication. This effect was triggered by residue 105 of 2B. The 2B K105A mutant FMDV was successfully rescued, and further studies showed that the pathogenicity was attenuated by mutation at site K105 of FMDV 2B. YTHDF2 also promoted FMDV replication through interferon‐dependent and interferon‐independent pathways. Moreover, YTHDF2‐deficient mice showed stronger resistance to FMDV infection. Our study reveals a potential mechanism for FMDV 2B negatively modulating innate immunity at transcriptional levels, promoting the understanding of immune evasion and YTHDF2 function in the FMDV infection process.