Zhang Jiyu, Zhang Liaoyuan, Liu Dakai, Shi Hongyan, Zhang Xin, Chen Jianfei, Yang Xiaoman, Zeng Miaomiao, Zhang Jialin, Feng Tingshuai, Zhu Xiaoyuan, Jing Zhaoyang, Ji Zhaoyang, Shi Da, Feng Li
State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
mBio. 2024 Dec 11;15(12):e0202824. doi: 10.1128/mbio.02028-24. Epub 2024 Oct 29.
Type Ι interferon (IFN) production mediated by retinoic acid-inducible gene 1 (RIG-I) and mitochondrial antiviral signaling protein (MAVS) is essential for antiviral innate immune responses. Here, we report the identification of a novel co-sensor for cytosolic nucleic acids: DEAD/H-box helicase 11 (DDX11), a member of the DExD/H (Asp-Glu-x-Asp/His)-box helicase family. Knockdown or knockout of DDX11 attenuated the ability of cells to increase IFN-β, IFN-stimulated gene 56, and C-X-C motif chemokine ligand 10 in response to SeV and poly (I:C) by blocking the activation of TANK-binding kinase 1 and IFN regulatory factor 3. Nucleic acid sensing by DDX11 was independent of the stimulator of IFN genes but was dependent on RIG-I and MAVS. DDX11 regulated RIG-I-MAVS-mediated IFN signaling by specifically interacting with nucleic acid, RIG-I, and MAVS to enhance RIG-I-double-strand RNA and RIG-I-MAVS binding affinity. Overall, our results identified a critical role for DDX11 in the innate immune response and provided molecular insights into the mechanisms by which DDX11 recognized cytosolic nucleic acid and interacted with RIG-Ι and MAVS for potent IFN signaling and antiviral immunity.
Innate immunity is the first and most rapid host defense against virus infection. Recognition of viral RNA by the retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs) initiates innate antiviral immune responses. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified DEAD/H-box helicase 11 (DDX11) as a positive regulator of the RIG-I-mitochondrial antiviral signaling protein (MAVS)-mediated signaling pathways. Mechanistically, we demonstrated that DDX11 bound to viral RNA, interacted with RIG-I, and promoted their binding to viral RNA. DDX11 also promoted the interaction between RIG-I and MAVS and activation of RIG-I-MAVS signaling. Overall, our results elucidate the role of DDX11 in RIG-I-MAVS-dependent signaling pathways and may shed light on innate immune gene regulation.
由视黄酸诱导基因1（RIG-I）和线粒体抗病毒信号蛋白（MAVS）介导的I型干扰素（IFN）产生对于抗病毒先天免疫反应至关重要。在此，我们报告鉴定出一种新型的胞质核酸共传感器：DEAD/H盒解旋酶11（DDX11），它是DExD/H（天冬氨酸-谷氨酸-x-天冬氨酸/组氨酸）盒解旋酶家族的成员。敲低或敲除DDX11会通过阻断TANK结合激酶1和IFN调节因子3的激活，减弱细胞对仙台病毒（SeV）和聚肌苷酸-聚胞苷酸（poly（I:C））产生IFN-β、IFN刺激基因56和C-X-C基序趋化因子配体10的能力。DDX11的核酸感应不依赖于IFN基因刺激物，但依赖于RIG-I和MAVS。DDX11通过与核酸、RIG-I和MAVS特异性相互作用来调节RIG-I-MAVS介导的IFN信号传导，以增强RIG-I与双链RNA以及RIG-I-MAVS的结合亲和力。总体而言，我们的结果确定了DDX11在先天免疫反应中的关键作用，并提供了关于DDX11识别胞质核酸以及与RIG-I和MAVS相互作用以实现有效IFN信号传导和抗病毒免疫机制的分子见解。
先天免疫是宿主针对病毒感染的第一道也是最快速的防御。视黄酸诱导基因1（RIG-I）样受体（RLRs）对病毒RNA的识别启动先天抗病毒免疫反应。病毒RNA与RLRs的结合及激活如何被调控仍不清楚。在本研究中，我们鉴定出DEAD/H盒解旋酶11（DDX11）是RIG-I-线粒体抗病毒信号蛋白（MAVS）介导的信号通路的正调控因子。从机制上讲，我们证明DDX11与病毒RNA结合，与RIG-I相互作用，并促进它们与病毒RNA的结合。DDX11还促进RIG-I与MAVS之间的相互作用以及RIG-I-MAVS信号传导的激活。总体而言，我们的结果阐明了DDX11在RIG-I-MAVS依赖性信号通路中的作用，并可能为先天免疫基因调控提供线索。
