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

Xu, Yan; Zhang, Youwen; Luo, Jia; Jiang, Sheng; Zhang, Jiajia; Liu, Xueliang; Shao, Qi; Cao, Qi; Zheng, Wanglong; Chen, Nanhua; Meurens, François; Zhu, Jianzhong

doi:10.3390/v13091829

Cited by 17 publications

(16 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study demonstrated that the cGAS is important in inhibiting PRRSV replication, consistent with previous studies ( 28 ). Their study suggested that cGAS and STING possess the anti-PRRSV effect.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

cGAS Restricts PRRSV Replication by Sensing the mtDNA to Increase the cGAMP Activity

Liu

Gao

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus that causes great economic losses globally to the swine industry. Innate immune RNA receptors mainly sense it during infection. As a DNA sensor, cyclic GMP-AMP synthase (cGAS) plays an important role in sensing cytosolic DNA and activating innate immunity to induce IFN-I and establish an antiviral cellular state. In contrast, the role of innate immune DNA sensors during PRRSV infection has not been elucidated. In this study, we found that cGAS facilitates the production of IFN-β during PRRSV infection. Western blot and virus titer assays suggested that cGAS overexpression suppressed the replication of multiple PRRSV strains, while knockout of cGAS increased viral titer and nucleocapsid protein expression. Besides, our results indicated that the mitochondria were damaged during PRRSV infection and leaked mitochondrial DNA (mtDNA) into the cytoplasm. The mtDNA in the cytoplasm co-localizes with the cGAS, and the cGAMP activity was increased when the cGAS was overexpressed during PRRSV infection. Furthermore, the cGAMP also possesses an anti-PRRSV effect. These results indicate for the first time that cGAS restricts PRRSV replication by sensing the mtDNA in the cytoplasm to increase cGAMP activity, which not only explains the molecular mechanism by which cGAS inhibits PRRSV replication but also provides research ideas for studying the role of the cGAS-STING signaling pathway in the process of RNA virus infection.

show abstract

Section: Discussionsupporting

confidence: 93%

“…Their study suggested that cGAS and STING possess the anti-PRRSV effect. Nevertheless, the mechanism is unclear ( 28 ). Our findings show that cGAS overexpression promotes IFN-β production during PRRSV infection at both the transcription and translation levels ( Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

cGAS Restricts PRRSV Replication by Sensing the mtDNA to Increase the cGAMP Activity

Liu

Gao

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Additionally, the porcine STING siRNA were synthesized based on our previous study (28). One day before transfection, 3D4/21 cells were plated into 24-well plates and cultured in growth medium.…”

Section: Asfv Infection and Sirna Treatmentmentioning

confidence: 99%

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

et al. 2022

Self Cite

View full text Add to dashboard Cite

African swine fever virus (ASFV) encodes more than 150 proteins, which establish complex interactions with the host for the benefit of the virus in order to evade the host’s defenses. However, currently, there is still a lack of information regarding the roles of the viral proteins in host cells. Here, our data demonstrated that ASFV structural protein p17 exerts a negative regulatory effect on cGAS-STING signaling pathway and the STING signaling dependent anti-HSV1 and anti-VSV functions. Further, the results indicated that ASFV p17 was located in ER and Golgi apparatus, and interacted with STING. ASFV p17 could interfere the STING to recruit TBK1 and IKKϵ through its interaction with STING. It was also suggested that the transmembrane domain (amino acids 39–59) of p17 is required for interacting with STING and inhibiting cGAS-STING pathway. Additionally, with the p17 specific siRNA, the ASFV induced IFN-β, ISG15, ISG56, IL-6 and IL-8 gene transcriptions were upregulated in ASFV infected primary porcine alveolar macrophages (PAMs). Taken together, ASFV p17 can inhibit the cGAS-STING pathway through its interaction with STING and interference of the recruitment of TBK1 and IKKϵ. Our work establishes the role of p17 in the immune evasion and thus provides insights on ASFV pathogenesis.

show abstract

“…Porcine alveolar macrophages (3D4/21, ATCC CRL-2843) were grown in RPMI 1640 (Hyclone Laboratories, Logan, UT, USA) supplemented with 10% FBS with 1% penicillin-streptomycin solution, and maintained at 37 °C with 5% CO2 in a humidified incubator. The viruses including a DNA virus Herpes Simplex Virus 1 (HSV1-GFP) as well as RNA viruses Vesicular Stomatitis Virus (VSV-GFP) and Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Viruses (HP-PRRSV XJ17-5-GFP and HP-PRRSV vaccine strain JXA1-R-GFP) were used as we previously reported [22][23][24].…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Interestingly, recent publications have suggested the relevance of the cGAS-STING pathway in the process of RNA virus infections [19][20][21][22]. However, whether Mn 2+ plays a role in the cGAS-STING pathway mediated anti-RNA virus infections is still largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Manganese Mediates its Antiviral Functions in a cGAS-STING Pathway Independent Manner

Sun¹,

Xu²,

Qiu³

et al. 2023

Preprint

View full text Add to dashboard Cite

The innate immune system is the first line of host defense sensing viral infection. Manganese (Mn) has recently been found to be involved in the activation of innate immune DNA sensing cGAS-STING pathway and subsequent anti-DNA virus function. However, whether Mn2+ mediates host defense against RNA viruses is still unclear. In the current study, we demonstrated that Mn2+ exhibited antiviral effects against various animal and human viruses including RNA viruses such as PRRSVs and the VSV as well as a DNA virus such as the HSV1 in a dose-dependent manner. Moreover, cGAS and STING were both investigated in the Mn2+ mediated antiviral roles using the knockout cells made by CRISPR-Cas9 approach. Unexpectedly, the results revealed that neither cGAS knockout nor STING knockout had any effect on Mn2+ mediated antiviral functions. Nevertheless, we verified that Mn2+ promoted the activation of cGAS-STING signaling pathway. These findings suggest that Mn2+ has broad spectrum antiviral activities in a cGAS-STING pathway independent manner. This study also provides significant insights into redundant mechanisms participating in the Mn2+ antiviral functions and also indicates new target for Mn2+ antiviral therapeutics.

show abstract

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

Cited by 17 publications

References 46 publications

cGAS Restricts PRRSV Replication by Sensing the mtDNA to Increase the cGAMP Activity

cGAS Restricts PRRSV Replication by Sensing the mtDNA to Increase the cGAMP Activity

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

Manganese Mediates its Antiviral Functions in a cGAS-STING Pathway Independent Manner

Contact Info

Product

Resources

About