African swine fever virus MGF360-11L negatively regulates cGAS-STING-mediated inhibition of type I interferon production

Abstract

The type I interferon (IFN-I) signaling pathway is an important part of the innate immune response and plays a vital role in controlling and eliminating pathogens. African swine fever virus (ASFV) encodes various proteins to evade the host’s natural immunity. However, the molecular mechanism by which the ASFV-encoded proteins inhibit interferon production remains poorly understood. In the present study, ASFV MGF360-11L inhibited cGAS, STING, TBK1, IKKε, IRF7 and IRF3-5D mediated activation of the IFN-β and ISRE promoters, accompanied by decreases in IFN-β, ISG15 and ISG56 mRNA expression. ASFV MGF360-11L interacted with TBK1 and IRF7, degrading TBK1 and IRF7 through the cysteine, ubiquitin–proteasome and autophagy pathways. Moreover, ASFV MGF360-11L also inhibited the phosphorylation of TBK1 and IRF3 stimulated by cGAS-STING overexpression. Truncation mutation analysis revealed that aa 167-353 of ASFV MGF360-11L could inhibit cGAS-STING-mediated activation of the IFN-β and ISRE promoters. Finally, the results indicated that ASFV MGF360-11L plays a significant role in inhibiting IL-1β, IL-6 and IFN-β production in PAM cells (PAMs) infected with ASFV. In short, these results demonstrated that ASFV MGF360-11L was involved in regulating IFN-I expression by negatively regulating the cGAS signaling pathway. In summary, this study preliminarily clarified the molecular mechanism by which the ASFV MGF360-11L protein antagonizes IFN-I-mediated antiviral activity, which will help to provide new strategies for the treatment and prevention of ASF.

African Swine Fever Virus EP364R and C129R Target Cyclic GMP-AMP To Inhibit the cGAS-STING Signaling Pathway

“…On the other hand, multiple viral proteins targeting the same molecules/innate immune pathways and providing functional redundancy are commonly observed and have been extensively reported for large DNA viruses such as ASFV and VACV. Degradation of TBK1 by ASFV I215L ( 26 ) and ASFV MGF 360-11L ( 32 ) and NF-κB inhibition by A238L, the homolog of IκB ( 80 ), and I215L ( 27 ) are a few examples of ASFV protein functional redundancy. In contrast, ASFV I215L is involved in the virus replication cycle ( 81 ) and host protein synthesis ( 82 ), and MGF 360-11L degrades IRF7 ( 32 ), which are nonredundant functions of ASFV proteins.…”

“…Degradation of TBK1 by ASFV I215L ( 26 ) and ASFV MGF 360-11L ( 32 ) and NF-κB inhibition by A238L, the homolog of IκB ( 80 ), and I215L ( 27 ) are a few examples of ASFV protein functional redundancy. In contrast, ASFV I215L is involved in the virus replication cycle ( 81 ) and host protein synthesis ( 82 ), and MGF 360-11L degrades IRF7 ( 32 ), which are nonredundant functions of ASFV proteins. In vaccinia virus (VACV), C4 and C16 proteins bind to lupus Ku autoantigen protein p70 (Ku70) to antagonize DNA-PK by binding to Ku and blocking Ku binding to DNA, reducing the production of cytokines and chemokines ( 83 ).…”

“…In contrast, ASFV I215L (E2 ubiquitin-conjugating enzyme) impairs IFN-β via the K63-linked ubiquitination of TBK1 and NF-κB signaling ( 26 , 27 ). Consequently, various ASFV proteins are involved in immune-suppressive mechanisms along with diverse target molecules in type I IFN and NF-κB signaling ( 28 – 32 ). However, the exact mechanism by which the ASFV protein targets cGAMP in type I IFN signaling is unknown.…”

Bovine delta papillomavirus E5 oncoprotein negatively regulates the cGAS-STING signaling pathway in cattle in a spontaneous model of viral disease

“…Although the cGAS-STING-mediated DNA-sensing signal is crucial for host defence against many viruses, especially DNA viruses, few viral components have been identified that specifically target this signaling pathway ( 9 ). Many human oncogenic viruses such as human papillomavirus (HPV) ( 1 , 10 – 13 ), many DNA viruses such as herpesvirus, pseudorabies virus ( 14 ), avian oncogenic herpesvirus ( 15 ), poxviruses such as fowlpox virus ( 16 ), and asfarviruses such as African swine fever virus ( 17 – 20 ) are known to be recognized by host pattern-recognition receptors and have been shown to subvert the cGAS-STING signaling pathway.…”

New Insights in the Interplay Between African Swine Fever Virus and Innate Immunity and Its Impact on Viral Pathogenicity

“…Strikingly, some key proteins of the IFN pathway are the target of multiple ASFV inhibitors. For instance, TBK1 is inhibited (or degraded) by E120R ( Liu H. et al, 2021 ), DP96R ( Wang et al, 2018 ), MGF-360-11L ( Yang et al, 2022 ), and A137R ( Sun et al, 2022 ). Similarly, JAK/STAT are targeted by MGF-360-9L ( Zhang et al, 2022 ) and MGF-505-7R ( Li et al, 2021b ).…”