State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China; College of Animal Science and Technology, Yangtze University, Jingzhou 434100, China.
Cell Rep. 2019 Jan 29;26(5):1258-1272.e4. doi: 10.1016/j.celrep.2019.01.029.
DExD/H-box helicase members are key receptors for recognizing viral nucleic acids, and they regulate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated type I interferon (IFN) production. Here, we report that the DExD/H-box helicase family member DExD/H-box RNA helicase 19 (DDX19) is a negative regulator of type I IFN production. Ectopic expression of DDX19 suppressed poly(I:C) (polyinosinic-polycytidylic acid)- and Sendai-virus-induced type I IFN production, whereas knockdown of DDX19 expression enhanced type I IFN production. Mechanistically, DDX19 inhibited TANK-binds kinase 1 (TBK1)- and inhibitor-κb kinase ε (IKKε)-mediated phosphorylation of interferon regulatory factor 3 (IRF3) by disrupting the interaction between TBK1 or IKKε and IRF3. Additionally, DDX19 recruited Lamtor2 and then formed the TBK1-IKKε-Lamtor2-DDX19-IRF3 complex to suppress IFN production by promoting TBK1 and IKKε degradation. We generated Ddx19 knockout mice using transcription activator-like effector nucleases (TALENs) and found that Ddx19 deficiency in vivo augmented type I IFN production, resulting in suppression of encephalomyocarditis virus replication. These data show that DDX19 is an important negative regulator of RLR-mediated type I IFN production.
DExD/H -box 解旋酶家族成员是识别病毒核酸的关键受体，它们调节视黄酸诱导基因 I（RIG-I）样受体（RLR）介导的 I 型干扰素（IFN）产生。在这里，我们报告 DExD/H 框解旋酶家族成员 DExD/H-Box RNA 解旋酶 19（DDX19）是 I 型 IFN 产生的负调节剂。DDX19 的异位表达抑制了 poly(I:C)（多聚肌苷酸-多聚胞苷酸）和仙台病毒诱导的 I 型 IFN 产生，而 DDX19 表达的敲低增强了 I 型 IFN 的产生。在机制上，DDX19 通过破坏 TBK1 或 IKKε 与 IRF3 之间的相互作用，抑制了 TANK 结合激酶 1（TBK1）和抑制剂-κB 激酶 ε（IKKε）介导的干扰素调节因子 3（IRF3）磷酸化。此外，DDX19 募集了 Lamtor2，然后形成了 TBK1-IKKε-Lamtor2-DDX19-IRF3 复合物，通过促进 TBK1 和 IKKε 的降解来抑制 IFN 的产生。我们使用转录激活因子样效应物核酸酶（TALENs）生成了 Ddx19 敲除小鼠，并发现体内的 Ddx19 缺失增强了 I 型 IFN 的产生，从而抑制了脑炎心肌炎病毒的复制。这些数据表明 DDX19 是 RLR 介导的 I 型 IFN 产生的重要负调节剂。
