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Journal ArticleDOI

Evolutionary Origins of cGAS-STING Signaling

TL;DR: The evolutionary origins of the cGAS-STING pathway are discussed, and the possibility that the ancestral functions of STING may have included activation of antibacterial immunity is considered.
About: This article is published in Trends in Immunology.The article was published on 2017-10-01. It has received 187 citations till now. The article focuses on the topics: Sting.
Citations
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Journal ArticleDOI
08 Mar 2019-Science
TL;DR: The latest advances uncovering how cGAS and STING control inflammatory responses and are themselves regulated are reviewed, suggesting a major clinical impact in areas of cancer immunotherapy and vaccine development.
Abstract: DNA is highly immunogenic. It represents a key pathogen-associated molecular pattern (PAMP) during infection. Host DNA can, however, also act as a danger-associated molecular pattern (DAMP) and elicit strong inflammatory responses. The cGAS-STING pathway has emerged as a major pathway that detects intracellular DNA. Here, we highlight recent advances on how cGAS and STING mediate inflammatory responses and how these are regulated, allowing cells to readily respond to infections and noxious agents while avoiding the inappropriate sensing of self-DNA. A particular focus is placed on the role of cGAS in the context of sterile inflammatory conditions. Manipulating cGAS or STING may open the door for new therapeutic strategies for the treatment of acute and chronic inflammation relevant to many human diseases.

493 citations


Cites background from "Evolutionary Origins of cGAS-STING ..."

  • ...CTT-independent responses may thus represent “primitive” forms of STING-mediated pathogen defense that may even rely on a distinct repertoire of antimicrobial effector functions not controlled by de novo gene expression (31)....

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  • ...This observation is interesting from an evolutionary perspective because the CTT is a rather recent functional element of STING, which emerged simultaneously with the IFN antiviral system (31)....

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Journal ArticleDOI
TL;DR: The cGAS-STING pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage as discussed by the authors, which has enabled the development of selective small-molecule inhibitors with the potential to target the CGS-STing axis in a number of inflammatory diseases.
Abstract: The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications

399 citations

Journal ArticleDOI
16 Nov 2017-Cell
TL;DR: It is shown that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells, and targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.

376 citations


Cites background from "Evolutionary Origins of cGAS-STING ..."

  • ...Of note, unlike the cGAS-STING axis, which evolved early in the metazoan lineage (Margolis et al., 2017), AIM2 is a much more recent development, in that it is only present in the mammalian class (Cridland et al., 2012)....

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  • ...Of note, unlike the cGAS-STING axis, which evolved early in the metazoan lineage (Margolis et al., 2017), AIM2 is a much more recent development, in that it is only present in the mammalian class (Cridland et al....

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Journal ArticleDOI
24 Oct 2018-Nature
TL;DR: It is concluded that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGas therefore represents a potential target for cancer prevention and therapy.
Abstract: Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING–IRF3–type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215—mediated by B-lymphoid tyrosine kinase—facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS–PARP1 interaction impedes the formation of the PARP1–Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

363 citations

Journal ArticleDOI
18 Sep 2019-Nature
TL;DR: cGAMP signalling in bacteria mediates anti-phage defence, as part of a genetic system suggested to be the ancient ancestor of the animal cGAS–STING innate immune pathway.
Abstract: The cyclic GMP-AMP synthase (cGAS)-STING pathway is a central component of the cell-autonomous innate immune system in animals1,2. The cGAS protein is a sensor of cytosolic viral DNA and, upon sensing DNA, it produces a cyclic GMP-AMP (cGAMP) signalling molecule that binds to the STING protein and activates the immune response3-5. The production of cGAMP has also been detected in bacteria6, and has been shown, in Vibrio cholerae, to activate a phospholipase that degrades the inner bacterial membrane7. However, the biological role of cGAMP signalling in bacteria remains unknown. Here we show that cGAMP signalling is part of an antiphage defence system that is common in bacteria. This system is composed of a four-gene operon that encodes the bacterial cGAS and the associated phospholipase, as well as two enzymes with the eukaryotic-like domains E1, E2 and JAB. We show that this operon confers resistance against a wide variety of phages. Phage infection triggers the production of cGAMP, which-in turn-activates the phospholipase, leading to a loss of membrane integrity and to cell death before completion of phage reproduction. Diverged versions of this system appear in more than 10% of prokaryotic genomes, and we show that variants with effectors other than phospholipase also protect against phage infection. Our results suggest that the eukaryotic cGAS-STING antiviral pathway has ancient evolutionary roots that stem from microbial defences against phages.

303 citations

References
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Journal ArticleDOI
15 Feb 2013-Science
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


"Evolutionary Origins of cGAS-STING ..." refers background in this paper

  • ...The cGAS-STING Pathway in Vertebrates Cyclic GMP–AMP synthase (cGAS), and its homologues in the OAS family, are atypical among innate immune sensors in being both receptors and biosynthetic enzymes [15,16]....

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Journal ArticleDOI
20 Jan 2011-Nature
TL;DR: A crucial role is revealed for the autophagy pathway and proteins in immunity and inflammation, and they balance the beneficial and detrimental effects of immunity andinflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
Abstract: Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

2,757 citations


"Evolutionary Origins of cGAS-STING ..." refers background in this paper

  • ...In mammalian cells, autophagy has recently been appreciated as an important innate immune pathway that appears to target and kill intracellular bacteria and viruses (reviewed in [97,98])....

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  • ...However, mice lacking most autophagy components are not impaired in their ability to control Mycobacterium tuberculosis infection [100]; indeed, many pathogens have evolved ways to counter autophagy [97,98]....

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Journal ArticleDOI
24 Jun 1994-Science
TL;DR: Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.
Abstract: Mice lacking the known subunit of the type I interferon (IFN) receptor were completely unresponsive to type I IFNs, suggesting that this receptor chain is essential for type I IFN-mediated signal transduction. These mice showed no overt anomalies but were unable to cope with viral infections, despite otherwise normal immune responses. Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.

2,438 citations


"Evolutionary Origins of cGAS-STING ..." refers background in this paper

  • ...Mice deficient in the type I IFN receptor are highly susceptible to most viral infections [6]....

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Journal ArticleDOI
02 Oct 2008-Nature
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

Journal ArticleDOI
08 Oct 2009-Nature
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