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

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.

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

Rheumatology and Immunology Research ◽

10.2478/rir-2021-0023 ◽

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.637399 ◽

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.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.748485 ◽

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.

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

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01226-3 ◽

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

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

Vaccines ◽

10.3390/vaccines7040197 ◽

2019 ◽

Vol 7 (4) ◽

pp. 197 ◽

Cited By ~ 2

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.

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The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.814709 ◽

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.

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A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling

Nature Communications ◽

10.1038/s41467-021-26240-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Daipayan Banerjee ◽

Kurt Langberg ◽

Salar Abbas ◽

Eric Odermatt ◽

Praveen Yerramothu ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Signal Transduction Pathway ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Damage Response

AbstractCyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Here we show that cGAMP activates DNA damage response (DDR) signaling independently of its canonical IFN pathways. Loss of cGAS dampens DDR signaling induced by genotoxic insults. Mechanistically, cGAS activates DDR in a STING-TBK1-dependent manner, wherein TBK1 stimulates the autophosphorylation of the DDR kinase ATM, with the consequent activation of the CHK2-p53-p21 signal transduction pathway and the induction of G1 cell cycle arrest. Despite its stimulatory activity on ATM, cGAMP suppresses homology-directed repair (HDR) through the inhibition of polyADP-ribosylation (PARylation), in which cGAMP reduces cellular levels of NAD+; meanwhile, restoring NAD+ levels abrogates cGAMP-mediated suppression of PARylation and HDR. Finally, we show that cGAMP also activates DDR signaling in invertebrate species lacking IFN (Crassostrea virginica and Nematostella vectensis), suggesting that the genome surveillance mechanism of cGAS predates metazoan interferon-based immunity.

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

Science ◽

10.1126/science.1240933 ◽

2013 ◽

Vol 341 (6148) ◽

pp. 903-906 ◽

Cited By ~ 553

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.

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The cyclic dinucleotide 2′3′-cGAMP induces a broad antibacterial and antiviral response in the sea anemone Nematostella vectensis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2109022118 ◽

2021 ◽

Vol 118 (51) ◽

pp. e2109022118

Author(s):

Shally R. Margolis ◽

Peter A. Dietzen ◽

Beth M. Hayes ◽

Stephen C. Wilson ◽

Brenna C. Remick ◽

...

Keyword(s):

Transcriptional Response ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Protein Product ◽

Sea Anemone ◽

Guanosine Monophosphate ◽

Interferon Response ◽

Nematostella Vectensis ◽

Type I ◽

Interferon Stimulated Genes

In mammals, cyclic dinucleotides (CDNs) bind and activate STING to initiate an antiviral type I interferon response. CDNs and STING originated in bacteria and are present in most animals. By contrast, interferons are believed to have emerged in vertebrates; thus, the function of CDN signaling in invertebrates is unclear. Here, we use a CDN, 2′3′ cyclic guanosine monophosphate-adenosine monophosphate (2′3′-cGAMP), to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA sequencing, we found that 2′3′-cGAMP induces robust transcription of both antiviral and antibacterial genes in N. vectensis. Many of the antiviral genes induced by 2′3′-cGAMP are homologs of vertebrate interferon-stimulated genes, implying that the interferon response predates the evolution of interferons. Knockdown experiments identified a role for NF-κB in specifically inducing antibacterial genes downstream of 2′3′-cGAMP. Some of these putative antibacterial genes were also found to be induced during Pseudomonas aeruginosa infection. We characterized the protein product of one of the putative antibacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved antibacterial activity. This work suggests that a broad antibacterial and antiviral transcriptional response is an evolutionarily ancestral output of 2′3′-cGAMP signaling in animals.

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TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2100225118 ◽

2021 ◽

Vol 118 (14) ◽

pp. e2100225118

Author(s):

Seoyun Yum ◽

Minghao Li ◽

Yan Fang ◽

Zhijian J. Chen

Keyword(s):

Viral Infections ◽

Adenosine Monophosphate ◽

Nuclear Factor Κb ◽

Cyclic Guanosine Monophosphate ◽

Immune Defense ◽

Guanosine Monophosphate ◽

Type I Interferons ◽

Type I ◽

Autophagy Induction ◽

Independent Functions

The induction of type I interferons through the transcription factor interferon regulatory factor 3 (IRF3) is considered a major outcome of stimulator of interferon genes (STING) activation that drives immune responses against DNA viruses and tumors. However, STING activation can also trigger other downstream pathways such as nuclear factor κB (NF-κB) signaling and autophagy, and the roles of interferon (IFN)-independent functions of STING in infectious diseases or cancer are not well understood. Here, we generated a STING mouse strain with a mutation (S365A) that disrupts IRF3 binding and therefore type I interferon induction but not NF-κB activation or autophagy induction. We also generated STING mice with mutations that disrupt the recruitment of TANK-binding kinase 1 (TBK1), which is important for both IRF3 and NF-κB activation but not autophagy induction (L373A or ∆CTT, which lacks the C-terminal tail). The STING-S365A mutant mice, but not L373A or ∆CTT mice, were still resistant to herpes simplex virus 1 (HSV-1) infections and mounted an antitumor response after cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) treatment despite the absence of STING-induced interferons. These results demonstrate that STING can function independently of type I interferons and autophagy, and that TBK1 recruitment to STING is essential for antiviral and antitumor immunity.

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