文献类型： 外文期刊

作者： Xu, Jian ¹ ; Liu, Li-Yuan ¹ ; Zhi, Fei-Jie ¹ ; Song, Yin-Juan ¹ ; Zhang, Zi-Hui ² ; Li, Bin ³ ; Zheng, Fu-Ying ¹ ; Gao, Peng-Cheng ¹ ; Zhang, Su-Zi ¹ ; Zhang, Yu-Yu ¹ ; Zhang, Ying ¹ ; Qiu, Ying ⁴ ; Jiang, Bo ⁵ ; Li, Yong-Qing ⁵ ; Peng, Chen ² ; Chu, Yue-Feng ¹ ;

作者机构： 1.Lanzhou Univ, Lanzhou Vet Res Inst, Chinese Acad Agr Sci, State Key Lab Anim Dis Control & Prevent,Coll Vet, Lanzhou, Peoples R China

2.China Agr Univ, Coll Vet Med, Natl Key Lab Vet Publ Hlth, Beijing, Peoples R China

3.Xinjiang Agr Univ, Coll Vet Med, Urumqi, Peoples R China

4.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol,Univ Chinese Acad Sci, Shanghai, Peoples R China

5.Beijing Acad Agr & Forestry Sci, Inst Anim Husb & Vet Med, Beijing, Peoples R China

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.