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

文献类型： 外文期刊

第一作者： Xu, Jian

作者： Xu, Jian;Liu, Li-Yuan;Zhi, Fei-Jie;Song, Yin-Juan;Zheng, Fu-Ying;Gao, Peng-Cheng;Zhang, Su-Zi;Zhang, Yu-Yu;Zhang, Ying;Chu, Yue-Feng;Zhang, Zi-Hui;Peng, Chen;Li, Bin;Zhang, Yu-Yu;Qiu, Ying;Jiang, Bo;Li, Yong-Qing

作者机构：

关键词： DDX5; N6-Methyladenosine; TLR2/4 Transcripts; Inflammation; Bacterial Infection

期刊名称：EMBO REPORTS （ 影响因子：7.7； 五年影响因子：8.6 ）

ISSN： 1469-221X

年卷期： 2024 年 25 卷 2 期

页码：

收录情况： SCI

摘要： 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.

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