Maintenance of cyclic GMP–AMP homeostasis by ENPP1 is involved in pseudorabies virus infection

Wang, Jiang; Lu, Shao-Fang; Wan, Bo; Ming, Sheng-Li; Li, Guoli; Su, Bing-Qian; Liu, Jiao‐Yang; Wei, Yushuang; Yang, Gangyi; Chu, Bei-Bei

doi:10.1016/j.molimm.2018.01.008

Cited by 29 publications

(22 citation statements)

References 46 publications

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“…The cGAS–STING DNA sensing pathway has previously been reported to detect PRV infection and activate downstream TBK1 and IRF3 proteins. This process leads to IFN-β production; however, it conversely hydrolyses cGAMP by ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) in PRV-infected and cGAMP-transfected cells, as well as inhibits IRF3 phosphorylation and IFN-β secretion [ 48 ]. Whether PRV could evade the cGAS–STING pathway through other mechanisms, particularly via the direct involvement of viral factors, has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

Miao

Rui

et al. 2020

Vet Res

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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.

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Section: Discussionmentioning

confidence: 99%

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

Miao

Rui

et al. 2020

Vet Res

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“…PRV-GFP, PRV-QXX and PRRSV-BJ4 were used as previously described [57,72,74]. VSV-GFP, NDV-GFP and H1N1-PR8 were gifts from Yong-Tao Li (Henan Agricultural University, China) [75].…”

Section: Cells and Virusesmentioning

confidence: 99%

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Wang

Ming

et al. 2020

PLoS Pathog

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Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases. Author summaryBRD4 has been well investigated in tumorigenesis for its contribution to chromatin remodeling and gene transcription. BRD4 inhibitors are used as promising chemotherapeutic drugs for cancer therapy. Here, we show a unique mechanism through which BRD4 inhibition broadly inhibits attachment of DNA and RNA viruses through DNA damage-dependent antiviral innate immune activation via the cGAS-STING pathway, in both cell culture and an animal model. STING-associated innate immune signaling has been considered to be a new possibility for cancer therapy, and STING agonists have been tested in early clinical trials. Our data identify BRD4 inhibitors as a potent therapy not only for viral infection but also for cancer immunotherapy. PLOS PATHOGENSPLOS Pathogens | https://doi.

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“…PK15, 3D4/21, Vero and HEK293T cells were cultured in Dulbecco's modified Eagle's medium (DMEM) (Gibco, Grand Island, NY, USA) supplemented with 10% (v/v) fetal bovine serum (FBS; Gibco) at 37°C in 5% CO 2 . PRV-QXX (virulent strain) and PRV-GFP (recombinant strain) were used as previously described [8].…”

Section: Cells Virus and Tissuesmentioning

confidence: 99%

“…cGAS thereafter catalyzes the generation of cGAMP, an intrinsic second messenger that activates stimulator of interferon genes protein (STING) to promote IFN expression dependent on the cGAS/STING/TBK1/IRF3 innate immune pathway. Contrary to cGAMP production by cGAS, ectonucleotide pyrophosphatase phosphodiesterase 1 can hydrolyze cGAMP to maintain homeostasis of the cGAMP reservoir and prevent IFN overactivation during PRV infection [8]. PRV can also evade IFNmediated innate immune response to facilitate virus infection [9], suggesting that interaction of PRV and its host is complicated and obscure.…”

Section: Introductionmentioning

confidence: 99%

Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection

Wang

Ming

et al. 2020

International Journal of Biological Macromolecules

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a b s t r a c tKeywords: PRV IFITMs GAS/STING/TBK1/IRF3 innate immune pathway Viral entry Interferon-inducible transmembrane proteins (IFITMs) restrict infection by several viruses, such as influenza A virus, West Nile virus and dengue virus. It has not been determined whether porcine IFITMs (pIFITMs) inhibit infection by pseudorabies virus (PRV), an enveloped, double-stranded DNA virus, which is the etiological agent of Aujeszky's disease in pigs. Here, we report that PRV infection elicited pIFITM1 expression in PK15 porcine kidney epithelial cells and 3D4/21 alveolar macrophages. pIFITM2 and pIFITM3 expression was only elevated in PK15 cells during PRV infection. Depletion of pIFITM1 using RNA interference, either in PK15 or in 3D4/21 cells, enhanced PRV infection while overexpression of pIFITM1 had the opposite effect. Knockdown of pIFITM2 and pIFITM3 did not influence PRV infection, suggesting that pIFITM2 and pIFITM3 are independent of PRV infection. PRV-induced pIFITM1 expression was dependent on the cGAS/STING/TBK1/IRF3 innate immune pathway and interferon-alpha receptor-1, suggesting that pIFITM1 is up-regulated by the type I interferon signaling pathway. The anti-PRV role of pIFITM1 was inhibited upon PRV entry. Our data demonstrate that pIFITM1 is a host restriction factor that inhibits PRV entry that may shed light on a strategy for prevention of PRV infection.

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Maintenance of cyclic GMP–AMP homeostasis by ENPP1 is involved in pseudorabies virus infection

Cited by 29 publications

References 46 publications

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection

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