Severe fever with thrombocytopenia syndrome virus induces lactylation of m6A reader protein YTHDF1 to facilitate viral replication

Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging infectious pathogen with a high fatality rate, is an enveloped tripartite segmented single-stranded negative-sense RNA virus. SFTSV infection is characterized by suppressed host innate immunity, proinflammatory cytokine storm, failure of B-cell immunity, and robust viral replication. m6A modification has been shown to play a role in viral infections. However, interactions between m6A modification and SFTSV infection remain poorly understood. Through MeRIP-seq, we identify m6A modifications on SFTSV RNA. We show that YTHDF1 can bind to m6A modification sites on SFTSV, decreasing the stability of SFTSV RNA and reducing the translation efficiency of SFTSV proteins. The SFTSV virulence factor NSs increases lactylation of YTHDF1 and YTHDF1 degradation, thus facilitating SFTSV replication. Our findings indicate that the SFTSV protein NSs induce lactylation to inhibit YTHDF1 as a countermeasure to host's YTHDF1-mediated degradation of m6A-marked viral mRNAs. YTHDF1 binds to m6A modification sites on SFTSV, decreasing the stability of SFTSV RNA and reducing translation efficiency of SFTSV proteins. SFTSV protein NSs promotes YTHDF1 lactylation to inhibit YTHDF1 as a countermeasure.Specific m6A modification sites are identified on SFTSV RNAs.YTHDF1 inhibits SFTSV RNA expression in an m6A-dependent manner.The viral virulence factor NSs upregulates YTHDF1 lactylation. YTHDF1 binds to m6A modification sites on SFTSV, decreasing the stability of SFTSV RNA and reducing translation efficiency of SFTSV proteins. SFTSV protein NSs promotes YTHDF1 lactylation to inhibit YTHDF1 as a countermeasure.