PRRs, including several regulators in the cytoplasm and nucleus, control innate immunity by activating or degrading key components of antiviral signaling. Innate immunity is one of the first barriers against pathogen invasion, and it is initiated to eliminate pathogens through the use of pattern recognition receptors (PRRs). Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. We found that DDX5 interacts with the N 6-methyladenosine (m6A) writer METT元 to regulate methylation of mRNA through affecting the m6A writer METT元–METTL14 heterodimer complex. However, its regulatory effect in antiviral innate immunity remains unclear. Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. Sealy, Writing – original draft, Writing – review & editing, 3 Cuiping Song, Resources, Writing – review & editing, 4 Xiaojia Wang, Conceptualization, Writing – original draft, 5 and Yongqing Li, Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review & editing 1, ¤ * Jian Xu, Conceptualization, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Writing – original draft, Writing – review & editing, 1 Yunhong Cai, Data curation, Formal analysis, Investigation, Methodology, Software, 1 ZhenBang Ma, Data curation, Investigation, Methodology, Resources, Visualization, 2 Bo Jiang, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, 1 Wenxiao Liu, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, 1 Jing Cheng, Resources, Validation, Visualization, 1 Nannan Guo, Methodology, Resources, Software, Visualization, 1 Zishu Wang, Investigation, Software, 2 Joshua E.
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