| Innate immune systems produce a series of cytokines to resist the virus invasion through the recognition of virus by pattern recognition receptors. During DNA virus infection, viral nucleic acids are recognized by DNA receptors, thereby initiating downstream signaling cascades and inducing IFN-I(type I interferons), and pro-inflammatory cytokines. As a DNA receptor, c GAS(cyclic GMP-AMP synthase) work together with stimululator of interferon genes(STING) to activate the innate immune signaling pathways after sensing DNA. Studies have shown that c GAS catalyzes the synthesis of c GAMP, which is a second messenger and can be recognized by STING, then STING recruits TBK1 and further activates and promotes the phosphorylation of IRF3 to induce the expression of IFN-I.Herpes simplex virus type I(HSV-1) VP24, a serine protease encoded by the UL26 gene, is an essential gene. When VP24 is deleted, viral genomic DNA can not be effectively packaged within the nucleocapsid and it seriously affects the mature of progeny virus particles. Literatures show that HSV-1 encoded multiple proteins involving in the immune evasion of host antiviral innate immunity. For the first time, to that VP24 was demonstrated to block the DNA sensing signaling pathway.In the present study, we found that VP24 dampened interferon stimulatory DNA(ISD) triggered IFN-β production and inhibited IFN-β promoter activation induced by c GAS-STING or STING respectively. Further study demonstrated that ectopic expression of VP24 selectively blocked IRF3 but not NF-κB promoter activation. In addition, VP24 downregulated ISD induced phosphorylation and dimerization of IRF3 during HSV-1 infection. The underlying molecular mechanism is that VP24 abrogates the interaction between TBK1 and IRF3. These results illustrate that VP24 blocks the production of IFN-β by inhibiting IRF3 activation which may represent a critical adaptation to enable viral effective replication within the host. |
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