The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity.
The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity.
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RNA 解旋酶 DDX5 通过调节 DHX58 和 NFκB 转录本上的 N6-甲基腺苷水平来抑制抗病毒先天免疫，从而促进病毒感染
DOI：
10.1371/journal.ppat.1009530
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发表时间：
2021-04
期刊：
影响因子：
6.7
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Xu J;Cai Y;Ma Z;Jiang B;Liu W;Cheng J;Guo N;Wang Z;Sealy JE;Song C;Wang X;Li Y
多功能DEAD-box解旋酶5 （DDX5）在转录调控中起重要作用，被多种病毒劫持，促进病毒复制。然而，其在抗病毒先天免疫中的调节作用尚不清楚。我们发现DDX5与n6 -甲基腺苷（m6A）写入者METTL3相互作用，通过影响m6A写入者METTL3 - mettl14异源二聚体复合物来调节mRNA的甲基化。同时，DDX5通过结合保守的uguggcag元件，在病毒感染后的先天反应中促进转录本DHX58、p65和IKKγ的m6A修饰和核输出。稳定的IKKγ和p65转录本发生ythdf2依赖的mRNA衰变，而DHX58的翻译被促进，导致DDX5在感染RNA病毒后通过阻断p65途径和激活DHX58- tbk1途径抑制抗病毒先天反应。此外，我们发现DDX5在体内抑制抗病毒先天免疫。我们的研究结果表明，DDX5通过促进抗病毒转录物的RNA甲基化从而促进病毒传播，从而作为先天免疫的负调节因子。DEAD-box解旋酶5 （DDX5）在癌症的发生和促进病毒传播中起着重要作用。然而，DDX5如何操纵宿主细胞过程以促进复制仍然知之甚少。在这项研究中，我们发现DDX5是一种负抗病毒调节剂，通过操纵先天免疫转录本的n6 -甲基腺苷（m6A）。DDX5首先招募RNA m6A“writer”METTL3来控制m6A writer复合物，然后在先天免疫应答中通过结合保守的UGCUGCAG元件特异性促进m6A修饰和DDX5结合转录本的核输出，最终以依赖ythdf2的方式导致抗病毒转录本的RNA衰变。因此，DDX5在细胞RNA代谢中发挥重要作用，负向调节先天免疫对病毒感染的反应。这是首次揭示DDX5作为介导n6 -甲基腺苷mRNA修饰的重要组分在调节先天免疫中的作用。
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. 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.
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