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, and Changjiang Weng

Cell Reports 26, 1258–1272  January 29, 2019

https://doi.org/10.1016/j.celrep.2019.01.029

In Brief

DExD/H-box helicase members are key receptors for recognizing viral nucleic acids and participate in regulating RLRmediated 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.

Highlights

·DDX19 suppresses IRF3 phosphorylation

·DDX19 competes with TBK1 or IKKε binding to the IAD domain of IRF3

·DDX19 recruits Lamtor2 to promote TBK1 and IKKεdegradation

·DDX19 inhibits type I IFN production and thus enhances viral replication

SUMMARY

DExD/H-box helicase members are key receptors for recognizing viral nucleic acids and they regulate RLR-mediated type I interferon (IFN) production. Here we report that the DExD/H-box helicase family member DDX19 is a negative regulator of type I IFN production. Ectopic expression of DDX19 suppressed poly(I:C)- and Sendai virus-induced type I IFN production, whereas knockdown of DDX19 expression enhanced type I IFN production. Mechanistically, DDX19 inhibited TBK1- and IKKε-mediated phosphorylation of 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 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.