Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2'3'-cyclic GMP-AMP (cGAMP). The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA.
View Article and Find Full Text PDFLow-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing.
View Article and Find Full Text PDFThe cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a critical innate immune pathway that, following engagement by DNA, promotes distinct immune effector responses that can impact virtually all aspects of tumorigenesis, from malignant cell transformation to metastasis. Here we address how natural tumor-associated processes and traditional cancer therapies are shaped by cGAS-STING signaling, and how this contributes to beneficial or detrimental outcomes of cancer. We consider current efforts to target the cGAS-STING axis in tumors and highlight new frontiers in cGAS-STING biology to inspire thinking about their connection to cancer.
View Article and Find Full Text PDFSolid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition.
View Article and Find Full Text PDFAutoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased levels of cGAMP and enhanced IFN-I signature. To identify disease mechanisms and potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients.
View Article and Find Full Text PDFThe recognition of DNA through the cGAS-STING pathway plays a critical role in antiviral immunity, but can also drive maladaptive immune responses underlying several pathological conditions. Despite its importance, understanding the organization of cGAS-STING signaling axis in the 3D space of a cell is relatively limited. In this review, we discuss recent progress in understanding the spatial coordination of DNA-induced cGAS-STING activity and its relevance in balancing innate immune responses toward (self-) DNA.
View Article and Find Full Text PDFCOVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs ). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome.
View Article and Find Full Text PDFDNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis-specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune response and infiltration of immune cells.
View Article and Find Full Text PDFRecognition of DNA is an evolutionarily highly conserved mechanism of immunity. In mammals, the cGAS-STING pathway plays a central role in coupling DNA sensing to the execution of innate immune mechanisms, both in contexts of infection as well as in noninfectious settings of cellular stress and injury. The indiscriminate ability of double-stranded DNA (dsDNA) to activate cGAS challenges our understanding on how engagement of this pathway is prevented on genomic self-DNA under homeostatic conditions.
View Article and Find Full Text PDFNat Rev Immunol
September 2021
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.
View Article and Find Full Text PDFCoupling DNA sensing to the initiation of immune responses necessitates auxiliary control mechanisms to avoid autoimmunity. A key factor is the exonuclease TREX1, which antagonizes DNA-mediated activation of cGAS. Two studies, by Mohr et al.
View Article and Find Full Text PDFNucleic acid sensing through pattern recognition receptors is critical for immune recognition of microbial infections. Microbial DNA is frequently methylated at the N position of adenines (m6A), a modification that is rare in mammalian host DNA. We show here how that m6A methylation of 5'-GATC-3' motifs augments the immunogenicity of synthetic double-stranded (ds)DNA in murine macrophages and dendritic cells.
View Article and Find Full Text PDFTwo studies published in this issue of JEM, by Lepelley et al. (https://doi.org/10.
View Article and Find Full Text PDFThe DNA sensor cyclic GMP-AMP synthase (cGAS) initiates innate immune responses following microbial infection, cellular stress and cancer. Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cGMP-AMP, which triggers the induction of inflammatory cytokines and type I interferons . cGAS is also present inside the cell nucleus, which is replete with genomic DNA, where chromatin has been implicated in restricting its enzymatic activity.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFPathogen-derived nucleic acids are crucial signals for innate immunity. Despite the structural similarity between those and host nucleic acids, mammalian cells have been able to evolve powerful innate immune signaling pathways that originate from the detection of cytosolic nucleic acid species, one of the most prominent being the cGAS-STING pathway for DNA and the RLR-MAVS pathway for RNA, respectively. Recent advances have revealed a plethora of regulatory mechanisms that are crucial for balancing the activity of nucleic acid sensors for the maintenance of overall cellular homeostasis.
View Article and Find Full Text PDFAn increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas.
View Article and Find Full Text PDFThe mammalian cyclic dinucleotide 2',3'-cGAMP is a potent inducer of innate immune responses produced upon detection of cytosolic DNA by cGAS. The mechanisms underlying the control of intracellular cGAMP levels remained unclear. In a new study, Eaglesham et al.
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