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Nature Reviews. Nephrology Sep 2022Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the... (Review)
Review
Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP-AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2',3'-cyclic GMP-AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS-STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS-STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.
Topics: DNA; Humans; Interferon Type I; Membrane Proteins; Nucleotidyltransferases; Signal Transduction
PubMed: 35732833
DOI: 10.1038/s41581-022-00589-6 -
Science (New York, N.Y.) Feb 2013The 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...
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.
Topics: Adenosine Triphosphate; Amino Acid Sequence; Animals; Cell Line, Tumor; Cyclic AMP; Cyclic GMP; Cytidine Triphosphate; Cytosol; DNA; Gene Knockdown Techniques; HEK293 Cells; Humans; Interferon Type I; Interferon-beta; Metabolic Networks and Pathways; Mice; Molecular Sequence Data; Nucleotidyltransferases
PubMed: 23258413
DOI: 10.1126/science.1232458 -
Journal of Molecular Cell Biology Dec 2021The cyclic GMP‒AMP synthase (cGAS)‒stimulator of interferon genes (STING) signaling pathway senses the presence of cytosolic DNA and, in turn, triggers downstream... (Review)
Review
The cyclic GMP‒AMP synthase (cGAS)‒stimulator of interferon genes (STING) signaling pathway senses the presence of cytosolic DNA and, in turn, triggers downstream signaling to induce the expression of inflammatory and type I interferon genes in immune cells. Whereas the innate immune function of the cGAS‒STING pathway is well studied over the past years, emerging evidence suggests that this signaling pathway may have additional functions beyond innate immune surveillance. Consistent with this notion, dysregulation of the cGAS‒STING signaling pathway in adipocytes, hepatocytes, and renal proximal tubule epithelial cells are associated with metabolic dysfunction, impaired energy homeostasis, and kidney diseases. In this review, we summarize current understanding of the cGAS‒STING pathway in several metabolic diseases such as obesity, insulin resistance, alcoholic and nonalcoholic fatty liver diseases, as well as acute kidney injury and chronic kidney disease. We also review the interaction between the cGAS‒STING pathway and lipid metabolism. Lastly, we discuss potential mechanisms by which cGAS‒STING signaling regulates metabolism and point toward future avenues of research targeting the cGAS‒STING pathway as possible means to treat common metabolic disorders.
Topics: Acute Kidney Injury; Humans; Interferon Type I; Membrane Proteins; Nucleotidyltransferases; Signal Transduction
PubMed: 34665236
DOI: 10.1093/jmcb/mjab066 -
The Journal of Biological Chemistry Jul 2023Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to... (Review)
Review
Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well as fundamental cellular functions such as autophagy, senescence, and apoptosis. Mutations leading to constitutive activation of STING cause devastating human diseases. Thus, the cGAS-STING pathway is of great interest because of its role in diverse cellular processes and because of the potential therapeutic implications of targeting cGAS and STING. Here, we review molecular and cellular mechanisms of STING signaling, and we propose a framework for understanding the immunological and other cellular functions of STING in the context of disease.
Topics: Humans; Signal Transduction; Nucleotidyltransferases; Inflammation; DNA; Cytosol; Immunity, Innate
PubMed: 37247757
DOI: 10.1016/j.jbc.2023.104866 -
Journal of Hematology & Oncology Apr 2019During tumor progression, a subset of cancer cells escape from immune surveillance and eventually develop into measurable tumor mass. Cancer immunotherapy eradicates... (Review)
Review
During tumor progression, a subset of cancer cells escape from immune surveillance and eventually develop into measurable tumor mass. Cancer immunotherapy eradicates tumor cells by enhancing multiple steps in cancer-immunity cycle including antigen presentation, T cell priming, activation, and immune killing activity. Immunotherapy has been verified as an effective strategy in multiple cancers, but some problems still exist in actual clinical practice such as frequent primary and adaptive resistance. Combination with other adjuvant therapies gives us a new perspective to overcome the emerging obstacles in immunotherapy application. Recently, a series of studies demonstrated that the vital component of host innate immunity - cGAS-STING pathway might play an important role in anti-cancer immunity. It is generally acknowledged that the downstream signals of cGAS-STING especially type I interferon (IFN) bridge innate immunity and adaptive immunity. Given the functions of type I IFN in promoting the maturation and migration of dendritic cells, enhancing cytotoxic T lymphocyte- or natural killer cell-mediated cytotoxicity effect, and protecting effector cells from apoptosis, we believe cGAS-STING agonist might be used as sensitizer for multiple immunotherapies such as cancer vaccine, immune checkpoint blockade, and chimeric antigen receptor T cell therapy. In this review, we highlight the latest understanding of cGAS-STING pathway and the advances of the combination therapy of STING agonist and immunotherapy.
Topics: Animals; Humans; Immunotherapy; Mice; Neoplasms; Nucleotidyltransferases
PubMed: 30935414
DOI: 10.1186/s13045-019-0721-x -
Molecular Cell May 20232',3'-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been...
2',3'-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2',3'-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.
Topics: Protein Serine-Threonine Kinases; Signal Transduction; Membrane Proteins; Nucleotidyltransferases; DNA; Immunity, Innate
PubMed: 37086726
DOI: 10.1016/j.molcel.2023.03.029 -
Zoological Research Jan 2023The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP... (Review)
Review
The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.
Topics: Animals; Immunity, Innate; Signal Transduction; Nucleotidyltransferases; DNA
PubMed: 36579404
DOI: 10.24272/j.issn.2095-8137.2022.464 -
EMBO Molecular Medicine Apr 2020Cytosolic double-stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid-sensing pattern recognition receptors. We study the...
Cytosolic double-stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid-sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA recognition and investigate the neuroprotective effect of cyclic GMP-AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that cerebral ischemia promoted the release of dsDNA into the cytosol, where it initiated inflammatory responses by activating the cGAS. A151 effectively reduced the expression of cGAS, absent in melanoma 2 (AIM2) inflammasome, and pyroptosis-related molecules, including caspase-1, gasdermin D, IL-1β, and IL-18. Furthermore, mice treated with A151 showed a dampened immune response to stroke, with reduced counts of neutrophils, microglia, and microglial production of IL-6 and TNF-α after MCAO. Moreover, A151 administration significantly reduced infarct volume, attenuated neurodeficits, and diminished cell death. Notably, the protective effect of A151 was blocked in a microglia-specific cGAS knockout mouse. These findings offer unique perspectives on stroke pathogenesis and indicate that inhibition of cGAS could attenuate brain inflammatory burden, representing a potential therapeutic opportunity for stroke.
Topics: Animals; Brain Ischemia; Cytosol; DNA; Inflammation; Ischemic Stroke; Mice; Neuroprotection; Nucleotidyltransferases
PubMed: 32239625
DOI: 10.15252/emmm.201911002 -
Immunity Dec 2013Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor mediating innate antimicrobial immunity. It catalyzes the synthesis of a noncanonical cyclic dinucleotide, 2',5'...
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor mediating innate antimicrobial immunity. It catalyzes the synthesis of a noncanonical cyclic dinucleotide, 2',5' cGAMP, that binds to STING and mediates the activation of TBK1 and IRF-3. Activated IRF-3 translocates to the nucleus and initiates the transcription of the IFN-β gene. The structure of mouse cGAS bound to an 18 bp dsDNA revealed that cGAS interacts with dsDNA through two binding sites, forming a 2:2 complex. Enzyme assays and IFN-β reporter assays of cGAS mutants demonstrated that interactions at both DNA binding sites are essential for cGAS activation. Mutagenesis and DNA binding studies showed that the two sites bind dsDNA cooperatively and that site B plays a critical role in DNA binding. The structure of mouse cGAS bound to dsDNA and 2',5' cGAMP provided insight into the catalytic mechanism of cGAS. These results demonstrated that cGAS is activated by dsDNA-induced oligomerization.
Topics: Animals; Binding Sites; Catalytic Domain; DNA; Humans; Mice; Models, Molecular; Nucleotides, Cyclic; Nucleotidyltransferases; Protein Binding; Protein Structure, Quaternary
PubMed: 24332030
DOI: 10.1016/j.immuni.2013.10.019 -
Journal of Molecular Cell Biology Sep 2022Pattern recognition receptors are critical for the sensing of pathogen-associated molecular patterns or danger-associated molecular patterns and subsequent mounting of... (Review)
Review
Pattern recognition receptors are critical for the sensing of pathogen-associated molecular patterns or danger-associated molecular patterns and subsequent mounting of innate immunity and shaping of adaptive immunity. The identification of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a major cytosolic DNA receptor is a milestone in the field of DNA sensing. The engagement of cGAS by double-stranded DNA from different origins, including invading pathogens, damaged mitochondria, ruptured micronuclei, and genomic DNA results in the generation of cGAMP and activation of stimulator of interferon genes, which thereby activates innate immunity mainly characterized by the activation of type I interferon response. In recent years, great progress has been made in understanding the subcellular localization and novel functions of cGAS. In this review, we particularly focus on summarizing the multifaceted roles of cGAS in regulating senescence, autophagy, cell stemness, apoptosis, angiogenesis, cell proliferation, antitumor effect, DNA replication, DNA damage repair, micronucleophagy, as well as cell metabolism.
Topics: DNA; Immunity, Innate; Interferon Type I; Membrane Proteins; Nucleotidyltransferases; Pathogen-Associated Molecular Pattern Molecules; Signal Transduction
PubMed: 35536585
DOI: 10.1093/jmcb/mjac031