PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3
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...
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BMC
2020-09-01
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Series: | Veterinary Research |
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Online Access: | http://link.springer.com/article/10.1186/s13567-020-00843-4 |
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doaj-75eded7a846141e9ab7415a0db1a4e52 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zongyi Bo Yurun Miao Rui Xi Qiuping Zhong Chenyi Bao Huan Chen Liumei Sun Yingjuan Qian Yong-Sam Jung Jianjun Dai |
spellingShingle |
Zongyi Bo Yurun Miao Rui Xi Qiuping Zhong Chenyi Bao Huan Chen Liumei Sun Yingjuan Qian Yong-Sam Jung Jianjun Dai PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3 Veterinary Research pseudorabies virus cGAS–STING UL13 serine/threonine kinase protein IRF3 |
author_facet |
Zongyi Bo Yurun Miao Rui Xi Qiuping Zhong Chenyi Bao Huan Chen Liumei Sun Yingjuan Qian Yong-Sam Jung Jianjun Dai |
author_sort |
Zongyi Bo |
title |
PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3 |
title_short |
PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3 |
title_full |
PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3 |
title_fullStr |
PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3 |
title_full_unstemmed |
PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3 |
title_sort |
prv ul13 inhibits cgas–sting-mediated ifn-β production by phosphorylating irf3 |
publisher |
BMC |
series |
Veterinary Research |
issn |
1297-9716 |
publishDate |
2020-09-01 |
description |
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. |
topic |
pseudorabies virus cGAS–STING UL13 serine/threonine kinase protein IRF3 |
url |
http://link.springer.com/article/10.1186/s13567-020-00843-4 |
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doaj-75eded7a846141e9ab7415a0db1a4e522020-11-25T03:13:31ZengBMCVeterinary Research1297-97162020-09-0151111610.1186/s13567-020-00843-4PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3Zongyi Bo0Yurun Miao1Rui Xi2Qiuping Zhong3Chenyi Bao4Huan Chen5Liumei Sun6Yingjuan Qian7Yong-Sam Jung8Jianjun Dai9MOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityMOE Joint International Research Laboratory of Animal Health and Food Safety, MOA Key Laboratory of Animal Bacteriology, College of Veterinary Medicine, Nanjing Agricultural UniversityAbstract 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.http://link.springer.com/article/10.1186/s13567-020-00843-4pseudorabies viruscGAS–STINGUL13 serine/threonine kinase proteinIRF3 |