Inhibition of cGAS-STING-TBK1 signaling pathway by DP96R of ASFV China 2018/1

• Published in: Biochemical and biophysical research communications 2018-11, Vol.506 (3), p.437-443
• Main Authors: Wang, Xixi, Wu, Jing, Wu, Yingtong, Chen, Hongjun, Zhang, Shoufeng, Li, Jinxiang, Xin, Ting, Jia, Hong, Hou, Shaohua, Jiang, Yitong, Zhu, Hongfei, Guo, Xiaoyu
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; African swine fever virus; African Swine Fever Virus - genetics; African Swine Fever Virus - metabolism; AMINO ACIDS; Animals; ASFV; cGAS; DNA; DP96R; DP96R protein; FEVER; Genes, Viral; HEK293 cell line; HEK293 Cells; Humans; I kappa B kinase beta; Interferon-beta; Interferon-beta - metabolism; Life sciences; MB21D1 protein, human; Membrane Proteins; Membrane Proteins - metabolism; MPYS protein, human; Médecine vétérinaire & santé animale; NF-kappa B; NF-kappa B - metabolism; NF-κB; Nucleotidyltransferases; Nucleotidyltransferases - metabolism; PHOSPHORYLATION; Protein Domains; Protein-Serine-Threonine Kinases; Protein-Serine-Threonine Kinases - metabolism; Sciences du vivant; Signal Transduction; STING protein; SWINE; TBK1; TBK1 protein; TBK1 protein, human; Type I IFN; Veterinary medicine & animal health; Viral Proteins; Viral Proteins - chemistry; Viral Proteins - metabolism; VIRUSES
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2018.10.103

African swine fever virus (ASFV) is a highly pathogenic large DNA virus that causes African swine fever (ASF) in domestic pigs and European wild boars with mortality rate up to 100%. The DP96R gene of ASFV encodes one of the viral virulence factors, yet its action mechanism remains unknown. In this study, we report that DP96R of ASFV China 2018/1 strain subverts type I IFN production in cGAS sensing pathway. DP96R inhibited the cGAS/STING, and TBK1 but not IRF3-5D mediated IFN-β and ISRE promoters activation. Furthermore, DP96R selectively blocked the activation of NF-κB promoter induced by cGAS/STING, TBK1, and IKKβ, but not by overexpression of p65. Moreover, DP96R inhibited phosphorylation of TBK1 stimulated by cGAS/STING activation, and TBK1-induced antiviral response. Finally, truncated mutation analysis demonstrated that the region spanning amino acids 30 to 96 of DP96R was responsible for the inhibitory activity. To our knowledge, this is for the first time that DP96R of ASFV China 2018/1 is reported to negatively regulate type I IFN expression and NF-κB signaling by inhibiting both TBK1 and IKKβ, which plays an important role in virus immune evasion. •DP96R is an inhibitor of cGAS-triggered type I IFNs induction and NF-κB activation.•DP96R inhibits the phosphorylation of TBK1 and TBK1-mediated antiviral responses.•The C-terminal domain of DP96R is responsible for its inhibitory effects.