The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3–METTL14 heterodimer complex. 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. 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. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. 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.
Author summary DEAD-box helicase 5 (DDX5) greatly contributes to cancer development and facilitation of viral propagation. However, how DDX5 manipulates host cell processes to facilitate replication remains poorly understood. In this study, we found DDX5 is a negative antiviral regulator through manipulating N6-methyladenosine (m6A) of transcripts in innate immunity. Firstly, DDX5 recruited the RNA m6A “writer” METTL3 to control the m6A writer complex, then specifically promoted m6A modification and nuclear export of DDX5 binding transcripts by binding conserved UGCUGCAG element in innate immune response, ultimately, leading to RNA decay of antiviral transcripts in a YTHDF2-dependent manner. Consequently, DDX5 played vital roles in cellular RNA metabolisms to negatively regulate innate immune response to viral infection. It is the first time to unravel DDX5 as an important component that mediates modification of N6-methyladenosine of mRNA in regulating innate immunity.