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Type I interferon (IFN)-mediated responses operate a pivotal role in the first line of host immune defense against viruses. Upon DNA virus infection, DNA sensing cyclic GMP-AMP synthase-STING signal pathway is a key event in the IFN-mediated antiviral response and also a target of viral immune evasion. African swine fever (ASF) is a highly contagious, cross-border viral disease that often confers fatalities in domestic and feral pigs of all ages. African swine fever virus (ASFV), a causative agent of ASF, is a nucleocytoplasmic large DNA virus that masks critical elements of host immune system by several encoded proteins. In this study, we report a novel immune evasion mechanism of ASFV B175L to block type I IFN signaling by targeting STING and 2'3'-cyclic GMP-AMP (2'3'-cGAMP). We found that ASFV B175L significantly inhibited the DNA virus-induced IFN-ß production and IFN-mediated signaling responses. The conserved zf-FCS motif of ASFV B175L competitively interacted with both cGAMP and the cyclic dinucleotide binding domain of STING. Remarkably, the R238 and Y240 amino acids of STING were crucial for interaction with ASFV B175L. Consequently, this interaction inhibits the interaction between cGAMP and STING, thereby inhibiting downstream signaling including STING polymerization and phosphorylation of TANK-binding kinase 1 and interferon regulatory factor 3 for antiviral signaling. Taken together, these results highlight the critical role of ASFV B175L in suppression of IFN responses and provide a new target to guide live-attenuated ASFV vaccine. [ABSTRACT FROM AUTHOR]

African swine fever virus (ASFV) is a highly pathogenic swine DNA virus with high mortality that causes African swine fever (ASF) in domestic pigs and wild boars. For efficient viral infection, ASFV has developed complex strategies to evade key components of antiviral innate immune responses. However, the immune escape mechanism of ASFV remains unclear. Upon ASFV infection, cyclic GMP-AMP (29,39-cGAMP) synthase (cGAS), a cytosolic DNA sensor, recognizes ASFV DNA and synthesizes the second messenger 2',3'-cGAMP, which triggers interferon (IFN) production to interfere with viral replication. In this study, we demonstrated a novel immune evasion mechanism of ASFV EP364R and C129R, which blocks cellular cyclic 2',3'-cGAMP-mediated antiviral responses. ASFV EP364R and C129R with nuclease homology inhibit IFN-mediated responses by specifically interacting with 2',3'-cGAMP and exerting their phosphodiesterase (PDE) activity to cleave 2',3'-cGAMP. Particularly notable is that ASFV EP364R had a region of homology with the stimulator of interferon genes (STING) protein containing a 2',3'-cGAMP-binding motif and point mutations in the Y76S and N78A amino acids of EP364R that impaired interaction with 2',3'-cGAMP and restored subsequent antiviral responses. These results highlight a critical role for ASFV EP364R and C129R in the inhibition of IFN responses and could be used to develop ASFV live attenuated vaccines. [ABSTRACT FROM AUTHOR]