scholarly journals Cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS), innate immune responses, and viral hepatitis

Hepatology ◽  
2014 ◽  
Vol 60 (3) ◽  
pp. 1098-1100 ◽  
Author(s):  
Eloi R. Verrier ◽  
Michaela U. Gack ◽  
Thomas F. Baumert
Keyword(s):  
Immune Responses ◽  
Viral Hepatitis ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Innate Immune Responses

scholarly journals Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses

Science ◽  
2013 ◽  
Vol 341 (6148) ◽  
pp. 903-906 ◽  
Author(s):  
Daxing Gao ◽  
Jiaxi Wu ◽  
You-Tong Wu ◽  
Fenghe Du ◽  
Chukwuemika Aroh ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Adaptor Protein ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Type I ◽  
Innate Immune Responses ◽  
Hiv Reverse Transcriptase

Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

scholarly journals BAF restricts cGAS on nuclear DNA to prevent innate immune activation

Science ◽  
2020 ◽  
Vol 369 (6505) ◽  
pp. 823-828 ◽  
Author(s):  
Baptiste Guey ◽  
Marilena Wischnewski ◽  
Alexiane Decout ◽  
Kristina Makasheva ◽  
Murat Kaynak ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nuclear Dna ◽  
Membrane Integrity ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Danger Signal ◽  
Physical Separation ◽  
Safeguard Mechanism

The appearance of DNA in the cytosol is perceived as a danger signal that stimulates potent immune responses through cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). How cells regulate the activity of cGAS toward self-DNA and guard against potentially damaging autoinflammatory responses is a fundamental biological question. Here, we identify barrier-to-autointegration factor 1 (BAF) as a natural opponent of cGAS activity on genomic self-DNA. We show that BAF dynamically outcompetes cGAS for DNA binding, hence prohibiting the formation of DNA-cGAS complexes that are essential for enzymatic activity. Upon acute loss of nuclear membrane integrity, BAF is necessary to restrict cGAS activity on exposed DNA. Our observations reveal a safeguard mechanism, distinct from physical separation, by which cells protect themselves against aberrant immune responses toward genomic DNA.

scholarly journals A noncanonical function of cGAMP in inflammasome priming and activation

2017 ◽  
Vol 214 (12) ◽  
pp. 3611-3626 ◽  
Author(s):  
Karen V. Swanson ◽  
Robert D. Junkins ◽  
Cathryn J. Kurkjian ◽  
Elizabeth Holley-Guthrie ◽  
Avani A. Pendse ◽  
...  
Keyword(s):  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Host Cells ◽  
Murine Cytomegalovirus ◽  
Inflammasome Activation ◽  
Mouse Cells ◽  
Molecular Patterns ◽  
Human And Mouse

Recognition of pathogen-associated molecular patterns and danger-associated molecular patterns by host cells is an important step in innate immune activation. The DNA sensor cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) binds to DNA and produces cGAMP, which in turn binds to stimulator of interferon genes (STING) to activate IFN-I. Here we show that cGAMP has a noncanonical function in inflammasome activation in human and mouse cells. Inflammasome activation requires two signals, both of which are activated by cGAMP. cGAMP alone enhances expression of inflammasome components through IFN-I, providing the priming signal. Additionally, when combined with a priming signal, cGAMP activates the inflammasome through an AIM2, NLRP3, ASC, and caspase-1 dependent process. These two cGAMP-mediated functions, priming and activation, have differential requirements for STING. Temporally, cGAMP induction of IFN-I precedes inflammasome activation, which then occurs when IFN-I is waning. In mice, cGAS/cGAMP amplify both inflammasome and IFN-I to control murine cytomegalovirus. Thus, cGAMP activates the inflammasome in addition to IFN-I, and activation of both is needed to control infection by a DNA virus.

scholarly journals Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

2021 ◽  
Vol 12 ◽  
Author(s):  
Eloi R. Verrier ◽  
Christelle Langevin
Keyword(s):  
Nucleic Acid ◽  
Current Knowledge ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Nucleic Acid Binding ◽  
Sting Pathway ◽  
Molecular Patterns

Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.

Oral Immune Activation by Disgust and Disease-Related Pictures

2015 ◽  
Vol 29 (3) ◽  
pp. 119-129 ◽  
Author(s):  
Richard J. Stevenson ◽  
Deborah Hodgson ◽  
Megan J. Oaten ◽  
Luba Sominsky ◽  
Mehmet Mahmut ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Negative Control ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Markers ◽  
Before And After ◽  
Secondary Analyses ◽  
Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

Innate immune responses and type 1 diabetes: A role for a long non-coding RNA?

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
MP Ashton ◽  
I Tan ◽  
L Mackin ◽  
C Elso ◽  
E Chu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Non Coding Rna ◽  
Long Non Coding Rna
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