Inhibition of cGAS-STING-TBK1 signaling pathway by DP96R of ASFV China 2018/1

Wang, Xixi; Wu, Jing; Wu, Yingtong; Chen, Hongjun; Zhang, Shoufeng; Li, Jinxiang; Xin, Ting; Ji, Hong; Hou, Shaohua; Jiang, Yao; Zhu, Hongfei; Guo, Xiaoyu

doi:10.1016/j.bbrc.2018.10.103

Cited by 100 publications

(100 citation statements)

References 31 publications

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“…Regarding porcine cGAS, it has been investigated directly in only one study (44) and for its antiviral properties in several other reports (45)(46)(47). We showed here that both porcine cGAS and IFI16 are capable of eliciting IFN signaling dependent on porcine STING, which is exchangeable to human STING (Figures 2, 3).…”

Section: Discussionmentioning

confidence: 65%

Porcine IFI16 Negatively Regulates cGAS Signaling Through the Restriction of DNA Binding and Stimulation

Zheng

Zhou

et al. 2020

Front. Immunol.

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The innate immunity DNA sensors have drawn much attention due to their significant importance against the infections with DNA viruses and intracellular bacteria. Among the multiple DNA sensors, IFI16, and cGAS are the two major ones, subjected to extensive studies. However, these two DNA sensors in livestock animals have not been well defined. Here, we studied the porcine IFI16 and cGAS, and their mutual relationship. We found that both enable STING-dependent signaling to downstream IFN upon DNA transfection and HSV-1 infection, and cGAS plays a major role in DNA signaling. In terms of their relationship, IFI16 appeared to interfere with cGAS signaling as deduced from both transfected and knockout cells. Mechanistically, IFI16 competitively binds with agonist DNA and signaling adaptor STING and thereby influences second messenger cGAMP production and downstream gene transcription. Furthermore, the HIN2 domain of porcine IFI16 harbored most of its activity and mediated cGAS inhibition. Thus, this study provides a unique insight into the porcine DNA sensing system.

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Section: Discussionmentioning

confidence: 65%

Porcine IFI16 Negatively Regulates cGAS Signaling Through the Restriction of DNA Binding and Stimulation

Zheng

Zhou

et al. 2020

Front. Immunol.

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“…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 – 10 ]. For instance, 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 ].…”

Section: Introductionmentioning

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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“…MGF360 and MGF 530 genes related with length variations in the genome have been implicated in the modulation of IFN-Is (Burrage et al 2004 ). MGFs protein including A276R, A528R, I329L, DP96L can inhibit IFN signaling by targeting TLR3, IRF3, cGAS-STING (Correia et al 2013 ; Golding et al 2016 ; Wang et al 2018 ). In this study, results demonstrated that MGF360-12L significantly inhibited IFN-β and NF-κB mRNA transcription and promoter activity following poly (I: C) or TNFα stimulation, accompanied by a decrease of IRF3, AP-1 mRNA expression, suggesting that MGF360-12L is able to inhibit IFN-Is expression.…”

Section: Discussionmentioning

confidence: 99%

“…The ASFV I329L gene was a functional viral Toll like receptor 3 (TLR3) homologue, which can inhibit the induction of IFN mediated by TIR domain-containing adaptor inducing interferon-β (TRIF) (Correia et al 2013 ). DP96R was reported to negatively regulate IFN-I expression and NF-κB signaling by inhibiting both TANK binding kinase-1 (TBK1) and Inhibitor of kappa B kinase β (IKKβ) (O’Donnell et al 2017 ; Wang et al 2018 ). Studies demonstrated that deletion of 12L , a member of MGF360 , resulted in induction of IFN-I (Reis et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

African Swine Fever Virus MGF360-12L Inhibits Type I Interferon Production by Blocking the Interaction of Importin α and NF-κB Signaling Pathway

Zhuo

Guo

et al. 2020

Virol. Sin.

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African swine fever (ASF) is an infectious transboundary disease of domestic pigs and wild boar and spreading throughout Eurasia. There is no vaccine and treatment available. Complex immune escape strategies of African swine fever virus (ASFV) are crucial factors affecting immune prevention and vaccine development. MGF360 genes have been implicated in the modulation of the IFN-I response. The molecular mechanisms contributing to innate immunity are poorly understood. In this study, we demonstrated that ASFV MGF360-12L ( MGF360 families 12L protein) significantly inhibited the mRNA transcription and promoter activity of IFN-β and NF-κB, accompanied by decreases of IRF3, STING, TBK1, ISG54, ISG56 and AP-1 mRNA transcription. Also, MGF360-12L might suppress the nuclear localization of p50 and p65 mediated by classical nuclear localization signal (NLS). Additionally, MGF360-12L could interact with KPNA2, KPNA3, and KPNA4, which interrupted the interaction between p65 and KPNA2, KPNA3, KPNA4. We further found that MGF360-12L could interfere with the NF-κB nuclear translocation by competitively inhibiting the interaction between NF-κB and nuclear transport proteins. These findings suggested that MGF360-12L could inhibit the IFN-I production by blocking the interaction of importin α and NF-κB signaling pathway, which might reveal a novel strategy for ASFV to escape the host innate immune response. Electronic supplementary material The online version of this article (10.1007/s12250-020-00304-4) contains supplementary material, which is available to authorized users.

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Inhibition of cGAS-STING-TBK1 signaling pathway by DP96R of ASFV China 2018/1

Cited by 100 publications

References 31 publications

Porcine IFI16 Negatively Regulates cGAS Signaling Through the Restriction of DNA Binding and Stimulation

Porcine IFI16 Negatively Regulates cGAS Signaling Through the Restriction of DNA Binding and Stimulation

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

African Swine Fever Virus MGF360-12L Inhibits Type I Interferon Production by Blocking the Interaction of Importin α and NF-κB Signaling Pathway

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