TLR2型
炎症
细胞生物学
TLR4型
生物
先天免疫系统
内质网
泛素
Toll样受体
免疫系统
免疫学
基因
遗传学
作者
Jian Xu,Liyuan Liu,Feijie Zhi,Yifang Song,Zihui Zhang,Li B,Fang Zheng,Ping Gao,S Zhang,Yuyu Zhang,Ying Zhang,Ying Qiu,Bo Jiang,Yongqing Li,Peng Chen,Y. I. Chu
标识
DOI:10.1038/s44319-023-00047-9
摘要
Abstract 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-κB 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.
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