State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
Front Immunol. 2022 Aug 10;13:956794. doi: 10.3389/fimmu.2022.956794. eCollection 2022.
DEAD-box RNA helicase 21 (DDX21), also known as RHII/Gu, is an ATP-dependent RNA helicase. In addition to playing a vital role in regulating cellular RNA splicing, transcription, and translation, accumulated evidence has suggested that DDX21 is also involved in the regulation of innate immunity. However, whether DDX21 induces or antagonizes type I interferon (IFN-I) production has not been clear and most studies have been performed through ectopic overexpression or RNA interference-mediated knockdown. In this study, we generated DDX21 knockout cell lines and found that knockout of DDX21 enhanced Sendai virus (SeV)-induced IFN-β production and IFN-stimulated gene (ISG) expression, suggesting that DDX21 is a negative regulator of IFN-β. Mechanistically, DDX21 competes with retinoic acid-inducible gene I (RIG-I) for binding to double-stranded RNA (dsRNA), thereby attenuating RIG-I-mediated IFN-β production. We also identified that the 217-784 amino acid region of DDX21 is essential for binding dsRNA and associated with its ability to antagonize IFN production. Taken together, our results clearly demonstrated that DDX21 negatively regulates IFN-β production and functions to maintain immune homeostasis.
DEAD-box RNA 解旋酶 21（DDX21），也称为 RHII/Gu，是一种依赖于 ATP 的 RNA 解旋酶。除了在调节细胞 RNA 剪接、转录和翻译中发挥重要作用外，越来越多的证据表明 DDX21 还参与调节先天免疫。然而，DDX21 是否诱导或拮抗 I 型干扰素（IFN-I）的产生尚不清楚，并且大多数研究都是通过异位过表达或 RNA 干扰介导的敲低来进行的。在这项研究中，我们生成了 DDX21 敲除细胞系，发现敲除 DDX21 增强了 Sendai 病毒（SeV）诱导的 IFN-β 产生和 IFN 刺激基因（ISG）表达，表明 DDX21 是 IFN-β 的负调节剂。从机制上讲，DDX21 与视黄酸诱导基因 I（RIG-I）竞争结合双链 RNA（dsRNA），从而减弱 RIG-I 介导的 IFN-β 产生。我们还确定 DDX21 的 217-784 个氨基酸区域对于结合 dsRNA 以及与其拮抗 IFN 产生的能力至关重要。总之，我们的研究结果清楚地表明，DDX21 负调节 IFN-β 的产生，并发挥维持免疫稳态的作用。
