Abstract
Cyclic GMP-AMP (cGAMP) synthase (cGAS) is an intracellular sensor of cytoplasmic viral DNA created during virus infection, which subsequently activates the stimulator of interferon gene (STING)-dependent type I interferon response to eliminate pathogens. In contrast, viruses have developed different strategies to modulate this signalling pathway. Pseudorabies virus (PRV), an alphaherpesvirus, is the causative agent of Aujeszky’s disease (AD), a notable disease that causes substantial economic loss to the swine industry globally. Previous reports have shown that PRV infection induces cGAS-dependent IFN-β production, conversely hydrolysing cGAMP, a second messenger synthesized by cGAS, and attenuates PRV-induced IRF3 activation and IFN-β secretion. However, it is not clear whether PRV open reading frames (ORFs) modulate the cGAS–STING-IRF3 pathway. Here, 50 PRV ORFs were screened, showing that PRV UL13 serine/threonine kinase blocks the cGAS–STING-IRF3-, poly(I:C)- or VSV-mediated transcriptional activation of the IFN-β gene. Importantly, it was discovered that UL13 phosphorylates IRF3, and its kinase activity is indispensable for such an inhibitory effect. Moreover, UL13 does not affect IRF3 dimerization, nuclear translocation or association with CREB-binding protein (CBP) but attenuates the binding of IRF3 to the IRF3-responsive promoter. Consistent with this, it was discovered that UL13 inhibits the expression of multiple interferon-stimulated genes (ISGs) induced by cGAS–STING or poly(I:C). Finally, it was determined that PRV infection can activate IRF3 by recruiting it to the nucleus, and PRVΔUL13 mutants enhance the transactivation level of the IFN-β gene. Taken together, the data from the present study demonstrated that PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3.
Highlights
During viral infection, host cells recognize pathogenassociated molecular patterns (PAMPs) or damageassociated molecular patterns (DAMPs) via pattern recognition receptors (PRRs) and elicit downstream cascades of antiviral innate immune responses [1,2,3]
UL13 blocks IFN‐β transactivation mediated by the cyclic GMP-AMP synthase (cGAS)– stimulator of interferon gene (STING) pathway To screen Pseudorabies virus (PRV) open reading frame (ORF) that regulate IFN-β production mediated by the cGAS–STING pathway, 50 PRV ORFs, including 6 US genes and 44 UL genes, were amplified
UL13 inhibits IFN‐β transactivation mediated by cGAS– STING via interferon response factor 3 (IRF3) targeting Upon recognition of viral DNA, cGAS leads to Cyclic GMP-AMP (cGAMP) synthesis; translocation of STING from the endoplasmic reticulum (ER) to the Golgi apparatus; phosphorylation of TANK-binding kinase 1 (TBK1), IRF3, IRF7, or NF-κB; and expression of IFNs [32]
Summary
Host cells recognize pathogenassociated molecular patterns (PAMPs) or damageassociated molecular patterns (DAMPs) via pattern recognition receptors (PRRs) and elicit downstream cascades of antiviral innate immune responses [1,2,3]. Cyclic GMP-AMP (cGAMP) synthase (cGAS) has been identified as a cytosolic DNA sensor and plays an important role in type I interferon responses. Upon sensing pathogen DNA, cGAS catalyses the synthesis of cGAMP, a. To counteract the antiviral effect of cGAS–STING signalling, viruses have evolved to different evasion strategies. Herpesviruses, a group of large dsDNA viruses, have been intensively studied [8,9,10]. Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes the ORF52 tegument protein and latency-associated nuclear antigen (LANA), which inhibit cGAS enzymatic activity via cGAS and/or DNA binding [11]. KSHV vIRF1 blocks the phosphorylation of STING by preventing its interaction with TBK1 and interrupts p300/
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