DDX19 Inhibits Type I Interferon Production by Disrupting TBK1-IKKε-IRF3 Interactions and Promoting TBK1 and IKKε Degradation
Kunli Zhang,
Yuanfeng Zhang,
Juan Xue,
Qingwen Meng,
Hongyang Liu,
Caihong Bi,
Changyao Li,
Liang Hu,
Huibin Yu,
Tao Xiong,
Yuying Yang,
Shangjin Cui,
Zhigao Bu,
Xijun He,
Jiangnan Li,
Li Huang,
Changjiang Weng
Affiliations
Kunli Zhang
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Yuanfeng Zhang
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Juan Xue
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
Qingwen Meng
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Hongyang Liu
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
Caihong Bi
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Changyao Li
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Liang Hu
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Huibin Yu
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Tao Xiong
College of Animal Science and Technology, Yangtze University, Jingzhou 434100, China
Yuying Yang
College of Animal Science and Technology, Yangtze University, Jingzhou 434100, China
Shangjin Cui
Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
Zhigao Bu
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Xijun He
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Jiangnan Li
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
Li Huang
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China; Corresponding author
Changjiang Weng
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China; Corresponding author
Summary: 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 helicase members are key receptors for recognizing viral nucleic acids and participate in regulating RLR-mediated type I IFN production. Zhang et al. show that DDX19 acts as a critical negative regulator of type I IFN production by disrupting TBK1-IKKε-IRF3 complex formation and recruiting Lamtor2 to degrade TBK1 and IKKε. Keywords: DDX19, IRF3, IKKε, Lamtor2, negative regulatory, type I IFN, TBK1
