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.
Highlights
The pathogen that causes African swine fever (ASF) is an enveloped, double-stranded DNA virus that exists in the cytoplasm [1, 2]
African swine fever virus (ASFV) MGF360‐11L inhibits activation of the IFN‐β and ISRE promoters To explore whether ASFV MGF360-11L could regulate factors in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway, we evaluated the effect of ASFV MGF360-11L on cGAS, STING, tank-binding kinase 1 (TBK1), interferon response factor 3 (IRF3)-5D, IKKε and IRF7 expression by dual-luciferase reporter assays
The results revealed that ASFV MGF360-11L inhibited IFN-β and ISRE activation because MGF360-11L inhibited the expression of cGAS/STING (Figure 1A), STING (Figure 1B), TBK1 (Figure 1C), IRF3-5D (Figure 1D), IKKε (Figure 1E) and IRF7 (Figure 1F) in a dose-dependent manner in HEK293 T cells, indicating that ASFV MGF360-11L efficiently inhibited the IFN-I response by regulating the cGASSTING pathway
Summary
The pathogen that causes African swine fever (ASF) is an enveloped, double-stranded DNA virus that exists in the cytoplasm [1, 2]. After cells are infected with a DNA virus, a cytoplasmic sensor detects the viral DNA [10, 11]. A variety of cytoplasmic DNA sensors have been identified, cyclic GMP-AMP synthase (cGAS) has been widely accepted for detecting cytoplasmic DNA in a variety of cell types [12,13,14]. After viral DNA is detected, cGAS catalyzes the synthesis of the second messenger GMP-AMP (cGAMP), which is bound to stimulator of interferon gene (STING), a type I interferon (IFN-I) that is triggered by the virus and is a key adaptor for inducing of the innate antiviral response [15, 16]. The expression of IFN-I and inflammatory factors is induced by IRF3 in the nucleus to activate the innate immune response [8, 17]
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