Chicken DNA Sensing cGAS-STING Signal Pathway Mediates Broad Spectrum Antiviral Functions

Li, Shuangjie; Yang, Jie; Zhu, Yuanyuan; Ji, Xingyu; Wang, Kun; Jiang, Sheng; Luo, Jia; Wang, Hui; Zheng, Wanglong; Chen, Nanhua; Ye, Jianqiang; Meurens, François; Zhu, Jianzhong

doi:10.3390/vaccines8030369

Cited by 24 publications

(33 citation statements)

References 45 publications

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“…Then, 2 3 -cGAMP, as a second message, activates the signaling adaptor STING to induce antiviral IFN response. However, accumulated evidence shows that cGAS-STING pathway harbors a broad range antiviral function [26,27]. The DNA pathway during PPRSV infection has not been investigated and its role remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

Zhang

Luo

et al. 2021

Viruses

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Porcine reproductive and respiratory syndrome virus (PRRSV) modulates host innate immunity which plays a key role against PRRSV infection. As a RNA virus, PRRSV is mainly sensed by innate immune RNA receptors, whereas the role of innate immune DNA sensors in the PRRSV infection has not been elucidated. Here, we investigated the roles of DNA sensing cGAS-STING pathway in both PRRSV infected Marc-145 cells and porcine macrophages. The results show that in Marc-145 cells, the stable expression of STING with or without stimulations exhibited anti-PRRSV activity, and STING knockout heightened PRRSV infection. In CD163-3D4/21 porcine macrophages, either expression of STING or stimulation of cGAS-STING signaling obviously suppressed PRRSV infection, whereas in STING knockdown macrophages, the PRRSV infection was upregulated. Our results clearly demonstrate that the host cGAS-STING signal exerts an important antiviral role in PRRSV infection.

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Section: Introductionmentioning

confidence: 99%

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

Zhang

Luo

et al. 2021

Viruses

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“…Here, we revealed for the first time that pS273R plays as a negative regulator in the cGAS-STING pathway via genomic ORF screening and confirming experiments. We also found that pS273R obviously promotes the replications of both DNA and RNA viruses, suggesting that pS273R facilitates their replications by damaging the cGAS-STING signaling which has been shown to have broad antiviral function (26). Surprisingly, our results showed that pS273R inhibits the cGAS-STING signaling pathway by targeting and impairing the function of IKK, suggesting that IKK is likely to play an important role in the cGAS-STING pathway.…”

Section: Discussionmentioning

confidence: 54%

The African swine fever virus protease pS273R inhibits DNA sensing cGAS-STING pathway by targeting IKKε

Luo

Jiang

et al. 2021

Preprint

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African swine fever virus (ASFV), a large and complex cytoplasmic double-stranded DNA virus, has developed multiple strategies to evade the antiviral innate immune responses. Cytosolic DNA arising from invading ASFV is mainly detected by the cyclic GMP-AMP synthase (cGAS) and then triggers a series of innate immune responses to prevent virus invasion. However, the immune escape mechanism of ASFV remains to be fully clarified. The pS273R of ASFV is a member of the SUMO-1-specific protease family and is crucial for valid virus replication. In this study, we identified pS273R as a suppressor of cGAS-STING pathway mediated type I interferon (IFN) production by ASFV genomic open reading frame screening. The pS273R was further confirmed as an inhibitor of IFN production as well as its downstream antiviral genes in cGAS-STING pathway. Mechanistically, pS273R greatly decreased the cGAS-STING signaling by targeting IKKe but not TBK1 and pS273R was found to disturb the interaction between IKKe and STING through its interaction with IKKe. Further, mutational analyses revealed that pS273R antagonized the cGAS-STING pathway by enzyme catalytic activity, which may affect the IKKe sumoylation state required for the interaction with STING. In summary, our results revealed for the first time that pS273R acts as an obvious negative regulator of cGAS-STING pathway by targeting IKKϵ via its enzymatic activity, which shows a new immune evasion mechanism of ASFV.

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“…Micro Protein PAGE Recovery Kit was from Sangon Biotech (Shanghai, China). HSV1-GFP, VSV-GFP, SeV-GFP, EMCV were used as we previously reported ( 31 ). Influenza type A virus (IAV) PR8 H1N1 and Swine IAV (SwIAV) H9N2 were provided by Dr. Hongjun Chen at Shanghai Veterinary Research Institute China.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Porcine RIG-I Like Receptors Revealed the Positive Regulation of RIG-I and MDA5 by LGP2

Li¹,

Yang²,

Zhu³

et al. 2021

Front. Immunol.

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The RLRs play critical roles in sensing and fighting viral infections especially RNA virus infections. Despite the extensive studies on RLRs in humans and mice, there is a lack of systemic investigation of livestock animal RLRs. In this study, we characterized the porcine RLR members RIG-I, MDA5 and LGP2. Compared with their human counterparts, porcine RIG-I and MDA5 exhibited similar signaling activity to distinct dsRNA and viruses, via similar and cooperative recognitions. Porcine LGP2, without signaling activity, was found to positively regulate porcine RIG-I and MDA5 in transfected porcine alveolar macrophages (PAMs), gene knockout PAMs and PK-15 cells. Mechanistically, LGP2 interacts with RIG-I and MDA5 upon cell activation, and promotes the binding of dsRNA ligand by MDA5 as well as RIG-I. Accordingly, porcine LGP2 exerted broad antiviral functions. Intriguingly, we found that porcine LGP2 mutants with defects in ATPase and/or dsRNA binding present constitutive activity which are likely through RIG-I and MDA5. Our work provided significant insights into porcine innate immunity, species specificity and immune biology.

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Chicken DNA Sensing cGAS-STING Signal Pathway Mediates Broad Spectrum Antiviral Functions

Cited by 24 publications

References 45 publications

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

The African swine fever virus protease pS273R inhibits DNA sensing cGAS-STING pathway by targeting IKKε

Analysis of Porcine RIG-I Like Receptors Revealed the Positive Regulation of RIG-I and MDA5 by LGP2

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