Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity
TL;DR: The finding that the levels of downstream antiviral genes induced by UL82-deficient HCMV were higher than those induced by wild-type HCMV were revealed, revealing an important mechanism of immune evasion by H CMV.
About: This article is published in Cell Host & Microbe.The article was published on 2017-02-08 and is currently open access. It has received 133 citations till now. The article focuses on the topics: STING complex & Human cytomegalovirus.
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TL;DR: This Review examines the ten most common strategies that viruses use to subvert the IFN response with examples from publications appearing in the last 10 years of Cell Host & Microbe.
313 citations
Cites background from "Human Cytomegalovirus Tegument Prot..."
...Similarly, inhibition by herpesviruses of the ER-located cellular factor STING, which is directly downstream cGAS and binds to cGAMP to become an active signaling platform for IFN induction (Chen et al., 2016), has also been described in another Cell Host & Microbe publication by Fu et al. (2017)....
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TL;DR: It is demonstrated that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways.
186 citations
Cites methods from "Human Cytomegalovirus Tegument Prot..."
...1-Homo.cGAS Laboratory of Yan-Yi Wang Fu et al., 2017 pCAGGS inserted with Homo sapiens, Myotis davidii, Pteropus alecto and Rhinolophus sinicus STING or S tag This Study N/A pQCXIH inserted with Rhinolophus sinicus STING or GFP tag This Study N/A Software and Algorithms Seqman DNASTAR http://www.dnastar.com SRA-blast SRA-blast https://blast.ncbi.nlm.nih.gov/Blast.cgi MEGA4 Mega http://www.megasoftware.net/mega4/ Genedoc Genedoc http://genedoc.software.informer.com/ RSEM RSEM http://deweylab.github.io/RSEM/ DESeq Bioconductor http://bioconductor.org/packages/ release/bioc/html/DESeq.html Prism software GraphPad https://www.graphpad.com ImageJ ImageJ https://imagej.nih.gov/ij/...
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...ACKNOWLEDGMENTS We thank Yan-Yi Wang (Wuhan Institute of Virology, CAS) for providing the human cGAS and STING plasmids, Chun-Fu Zheng (School of Basic Medical Sciences, FujianMedical University) for theHSV-luciferase virus, andGary Crameri and Justin Ng for leading the team that helped to collect the Pa bat tissues for this study....
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...The STING sequence of Homo sapiens was amplified from HA-STING plasmid, which was generously provided by Yan-Yi Wang, Wuhan Institute of Virology, CAS, China....
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...1-Homo.cGAS Laboratory of Yan-Yi Wang Fu et al., 2017 pCAGGS inserted with Homo sapiens, Myotis davidii, Pteropus alecto and Rhinolophus sinicus STING or S tag This Study N/A pQCXIH inserted with Rhinolophus sinicus STING or GFP tag This Study N/A Software and Algorithms Seqman DNASTAR…...
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TL;DR: This work identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response and found that the M protein interacted with the central adaptor protein MAVS in the innateimmune response pathways.
Abstract: A novel SARS-related coronavirus (SARS-CoV-2) has recently emerged as a serious pathogen that causes high morbidity and substantial mortality. However, the mechanisms by which SARS-CoV-2 evades host immunity remain poorly understood. Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.
126 citations
TL;DR: A comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states is provided.
Abstract: Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.
120 citations
TL;DR: This study demonstrated that HSV-1 tegument protein VP22 counteracts the cGAS/STING-mediated DNA-sensing antiviral innate immunity signaling pathway by inhibiting the enzymatic activity of cGas.
Abstract: Cytosolic DNA arising from intracellular pathogens is sensed by cyclic GMP-AMP synthase (cGAS) and triggers a powerful innate immune response. However, herpes simplex virus 1 (HSV-1), a double-stranded DNA virus, has developed multiple mechanisms to attenuate host antiviral machinery and facilitate viral infection and replication. In the present study, we found that HSV-1 tegument protein VP22 acts as an inhibitor of cGAS/stimulator of interferon genes (cGAS/STING)-mediated production of interferon (IFN) and its downstream antiviral genes. Our results showed that ectopic expression of VP22 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Infection with wild-type (WT) HSV-1, but not VP22-deficient virus (ΔVP22), inhibited immunostimulatory DNA (ISD)-induced activation of the IFN signaling pathway. Further study showed that VP22 interacted with cGAS and inhibited the enzymatic activity of cGAS. In addition, stable knockdown of cGAS facilitated the replication of ΔVP22 virus but not the WT. In summary, our findings indicate that HSV-1 VP22 acts as an antagonist of IFN signaling to persistently evade host innate antiviral responses.IMPORTANCE cGAS is very important for host defense against viral infection, and many viruses have evolved ways to target cGAS and successfully evade the attack by the immune system of their susceptible host. This study demonstrated that HSV-1 tegument protein VP22 counteracts the cGAS/STING-mediated DNA-sensing antiviral innate immunity signaling pathway by inhibiting the enzymatic activity of cGAS. The findings in this study will expand our understanding of the interaction between HSV-1 replication and the host DNA-sensing signaling pathway.
116 citations
Cites background from "Human Cytomegalovirus Tegument Prot..."
...HFF cells contain the complete GAS/STING pathway, which is the major pathway activated by DNA transfection or DNA virus infection (30, 31)....
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References
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TL;DR: Results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP, which belongs to the nucleotidyltransferase family.
Abstract: The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.
3,096 citations
TL;DR: The identification of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes is reported, implying a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.
Abstract: The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-kappaB and IRF3 transcription pathways to induce expression of type I interferon (IFN-alpha and IFN-beta ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-beta, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPbeta), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit STING's ability to stimulate expression of IFN-beta. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.
2,319 citations
TL;DR: It is shown that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection.
Abstract: The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting-knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.
2,042 citations
TL;DR: Depletion of VISA inhibits virus-triggered and RIG-I-mediated activation of IRF-3, NF-kappaB, and the IFN-beta promoter, suggesting that VISA plays a central role in virus- Triggered TLR3-independent IFn-beta signaling.
1,692 citations
TL;DR: The results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity.
1,201 citations