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.

scholarly journals Regulation of cGAS-STING pathway - Implications for systemic lupus erythematosus

2021 ◽  
Vol 2 (3) ◽  
pp. 173-184
Author(s):  
Audrey M. Hagiwara ◽  
Richard E. Moore ◽  
Daniel J. Wallace ◽  
Mariko Ishimori ◽  
Caroline A. Jefferies
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Systemic Lupus ◽  
Downstream Signaling ◽  
Potential Therapeutic Application ◽  
Sting Pathway

Abstract Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the “interferonopathies.” Recently, the cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have been identified as having important, if not central, roles in driving IFN-I expression in response to self-DNA. This review highlights the many ways in which this pathway is regulated in order to prevent self-DNA recognition and underlines the importance of maintaining tight control in order to prevent autoimmune disease. We will discuss the murine and human studies that have implicated the cGAS-STING pathway as being an important contributor to breakdown in tolerance in SLE and highlight the potential therapeutic application of this knowledge for the treatment of SLE.

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 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 The cGAS–STING pathway: more than fighting against viruses and cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Terigen Bao ◽  
Jia Liu ◽  
Jiyan Leng ◽  
Lu Cai
Keyword(s):  
Inflammatory Diseases ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Antiviral Responses ◽  
Inflammatory Conditions ◽  
Inflammatory Status ◽  
Sting Pathway ◽  
Inflammatory Molecules

AbstractIn the classic Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, downstream signals can control the production of type I interferon and nuclear factor kappa-light-chain-enhancer of activated B cells to promote the activation of pro-inflammatory molecules, which are mainly induced during antiviral responses. However, with progress in this area of research, studies focused on autoimmune diseases and chronic inflammatory conditions that may be relevant to cGAS–STING pathways have been conducted. This review mainly highlights the functions of the cGAS–STING pathway in chronic inflammatory diseases. Importantly, the cGAS–STING pathway has a major impact on lipid metabolism. Different research groups have confirmed that the cGAS–STING pathway plays an important role in the chronic inflammatory status in various organs. However, this pathway has not been studied in depth in diabetes and diabetes-related complications. Current research on the cGAS–STING pathway has shown that the targeted therapy of diseases that may be caused by inflammation via the cGAS–STING pathway has promising outcomes.

scholarly journals Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Kunli Zhang ◽  
Sutian Wang ◽  
Hongchao Gou ◽  
Jianfeng Zhang ◽  
Chunling Li
Keyword(s):  
Signaling Pathway ◽  
Adenosine Monophosphate ◽  
Degradation Process ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Research Progress ◽  
Type I ◽  
Type I Ifn ◽  
Major Pathway ◽  
Sting Pathway

Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

scholarly journals Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Meixiao Zhan ◽  
Xiangrong Yu ◽  
Wei Zhao ◽  
Yongjun Peng ◽  
Shaojun Peng ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Near Infrared ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Ferrous Sulfide ◽  
Tumor Tissues ◽  
Ecm Degradation ◽  
Sting Pathway ◽  
Liposome Surface

AbstractRegulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome. Graphical Abstract

scholarly journals miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 197 ◽  
Author(s):  
Abid Ullah Shah ◽  
Yanan Cao ◽  
Naila Siddique ◽  
Jian Lin ◽  
Qian Yang
Keyword(s):  
Dendritic Cells ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Mouse Bone Marrow ◽  
Cytokine Detection ◽  
Sting Pathway ◽  
Factor Α ◽  
Antigen Presenting ◽  
And Control

The Cytosine–phosphate–guanosine (CpG) motif, which is specifically recognized intracellularly by dendritic cells (DCs), plays a crucial role in regulating the innate immune response. MicroRNAs (miRNAs) can strongly influence the antigen-presenting ability of DCs. In this study, we examine the action of miRNAs on CpG-stimulated and control DCs, as well as their effect on cyclic guanosine monophosphate-adenosine monophosphate (GMP–AMP) synthase (cGAS) and the stimulator of interferon genes (STING) signal pathway. Firstly, we selected miRNAs (miR-29a and miR-378b) based on expression in CpG-stimulated mouse bone marrow-derived dendritic cells (BMDCs). Secondly, we investigated the functions of miR-29a and miR-378b on CpG-stimulated and unstimulated BMDCs. The results showed that miR-29a and miR-378b increased expression of both the immunoregulatory DC surface markers (CD86 and CD40) and the immunosuppressive molecule CD273 by DCs. Thirdly, cytokine detection revealed that both miR-29a and miR-378b enhanced interferon-β (IFN-β) expression while suppressing tumor necrosis factor-α (TNF-α) production. Finally, our results suggest that miR-378b can bind TANK-binding kinase binding protein 1 (TBKBP1) to activate the cGAS/STING signaling pathway. By contrast, miR-29a targeted interferon regulatory factor 7 (IRF7) and promoted the expression of STING. Together, our results provide insight into the molecular mechanism of miRNA induction by CpG to regulate DC function.

scholarly journals Scavenging nucleic acid debris to combat autoimmunity and infectious disease

2016 ◽  
Vol 113 (35) ◽  
pp. 9728-9733 ◽  
Author(s):  
Eda K. Holl ◽  
Kara L. Shumansky ◽  
Luke B. Borst ◽  
Angela D. Burnette ◽  
Christopher J. Sample ◽  
...  
Keyword(s):  
Immune System ◽  
Nucleic Acid ◽  
Innate Immune ◽  
Nucleic Acid Binding ◽  
Downstream Effector ◽  
Wide Range ◽  
Molecular Patterns ◽  
Dying Cells ◽  
Damage Associated Molecular Patterns ◽  
Lethal Doses

Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal’s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.

scholarly journals The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

2022 ◽  
Vol 12 ◽  
Author(s):  
Nanxin Liu ◽  
Xiaoxiao Pang ◽  
Hua Zhang ◽  
Ping Ji
Keyword(s):  
Bacterial Infection ◽  
Viral Infection ◽  
Signaling Pathway ◽  
Bacterial Infections ◽  
Core Protein ◽  
Bacterial Species ◽  
Adenosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Sting Pathway

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host.

scholarly journals Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Patrícia R S Rodrigues ◽  
Aljawharah Alrubayyi ◽  
Ellie Pring ◽  
Valentina M T Bart ◽  
Ruth Jones ◽  
...  
Keyword(s):  
Immune Responses ◽  
Current Knowledge ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Innate Immunology ◽  
Viral Pathogen ◽  
Health Crisis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Abstract The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

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