DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex, which adds N6-methyladenosine to transcripts of toll-like receptor (TLR) 2 and TLR4, promoting their decay via YTHDF2-mediated RNA degradation, resulting in reduced expression of TLR2/4. Upon bacterial infection, DDX5 is recruited to Hrd1 at the endoplasmic reticulum in an MyD88-dependent manner and is degraded by the ubiquitin-proteasome pathway. This process disrupts the DDX5 m6A writing complex and halts m6A modification as well as degradation of TLR2/4 mRNAs, thereby promoting the expression of TLR2 and TLR4 and downstream NF-kappa B activation. The role of DDX5 in regulating inflammation is also validated in vivo, as DDX5- and METTL3-KO mice exhibit enhanced expression of inflammatory cytokines. Our findings show that DDX5 acts as a molecular switch to regulate inflammation during bacterial infection and shed light on mechanisms of quiescent inflammation during homeostasis. DDX5 serves as a molecular switch to regulate inflammation during bacterial infection. DDX5 promotes the modification of TLR2/4 mRNA with N6-methyladenosine, thereby triggering their degradation and reducing subsequent NF-kappa B-dependent inflammatory responses.DDX5 coordinates the formation of an m6A writer complex with METTL3 and METTL14 to degrade TLR2/4 mRNA. DDX5 is recruited to and degraded by endoplasmic reticulum-localized Hrd1 via the ubiquitin-proteasome pathway. DDX5 degradation disrupts the DDX5-METTL3-METTL14 complex and halts YTHDF2-dependent degradation of TLR2/4 transcripts. DDX5 serves as a molecular switch to regulate inflammation during bacterial infection. DDX5 promotes the modification of TLR2/4 mRNA with N6-methyladenosine, thereby triggering their degradation and reducing subsequent NF-kappa B-dependent inflammatory responses.