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Although it was known for decades that type I interferons are crucial for antiviral immunity, it was not until the discovery of cGAS and cGAMP signalling in 2013 that we understood how cytosolic DNA induces them in infected cells, as explained by Andrea Ablasser.

Chemotherapy-induced death of colon cancer cells causes ATP release triggering P2X4 to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders them sensitive to mTOR inhibition.

The cGAS–STING signalling pathway is a critical driver of chronic inflammation and functional decline during ageing, and could be targeted to halt neurodegenerative processes during old age.

The cGAS–STING pathway has a central role in the pathogenesis of severe COVID-19 by driving the increase in type I interferons that occurs in the later stages of SARS-CoV-2 infection.

The ubiquitin proteasomal system degrades nuclear cGAS in cycling cells.

The STING protein aids intracellular defences by triggering inflammation. Studies that uncover how STING is activated might lead to strategies for targeting this protein in the treatment of cancer or autoimmune diseases.

Samson and Ablasser review the roles of the cGAS–STING pathway in cancer and efforts to target this signaling axis therapeutically.

The detection of cytosolic DNA by the sensor cGAS triggers potent antiviral responses. New data now propose that cGAS is regulated on a post-translational level by glutamylation.

Using cryo-electron microscopy, the authors determine the structure of cGAS bound to nucleosomes and present evidence for the mechanism by which nucleosome binding to cGAS prevents cGAS dimerization and its binding to free double-stranded DNA.

The adaptor protein AP-1 controls the shutdown of STING signalling through a mechanism in which AP-1 recognizes a dileucine motif in phosphorylated STING, which leads to targeted transport of STING to the endolysosomal system for degradation.

After binding double-stranded RNA, RIG-I induces production of type 1 interferon. Hornung and colleagues find that RIG-I detects viral DNA via double-stranded RNA intermediates generated by RNA polymerase III.

This paper shows that the protein AIM2 (absent in melanoma 2) is a receptor of cytoplasmic DNA and the double-stranded DNA vaccinia virus, and is a component of the inflammasome pathway for caspase-1 activation.

The cGAS–STING pathway drives innate immune activation in response to cytosolic DNA. This is important for immunity to bacteria and viruses, but aberrant cGAS–STING activity is also linked to inflammatory disease. Here, Ablasser and colleagues discuss how cGAS–STING signalling contributes to various autoimmune, inflammatory and degenerative diseases and describe the novel therapeutics targeting this pathway.

Ablasser and Hur review the emerging literature on regulation of the sensing of cytosolic DNA and RNA via cGAS and RLRs.

The cGAS/STING signalling pathway is responsible for sensing intracellular DNA and activating downstream inflammatory genes. Here the authors show mouse primary T cells and T leukaemia are hyperresponsive to STING agonist, and this strong STING signalling is associated with apoptosis induction.

Glück et al. find that the DNA-sensing component cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments produced in senescent cells leading to STING-mediated production of SASPs, which promotes paracrine senescence.

Cyclic dinucleotides (CDNs) are potent activators of the innate immune sensor STING. The identification of a CDN importer sheds new light on the regulation of extracellular CDNs.

New data show that the interferon-induced gene product IFIT1 is a sensor for 5′-triphosphorylated RNA of viral origin and that it functions within a larger IFIT complex to inhibit viral replication.

The presence of nucleic acids in the cytosol alerts the cell to viral infection or damaged self. The oligoadenylate synthase (OAS) proteins and cyclic GMP–AMP synthase (cGAS) are enzymes that detect this danger and promote antiviral immunity. Recent structural studies reveal that these enzymes have a common mechanism of action and probably the same evolutionary origin.

The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes (STING) protein may help to develop therapies for the treatment of autoinflammatory disease.

Bacterial DNA from Listeria monocytogenes infection is packaged within extracellular vesicles and induces paracrine cGAS–STING signalling in bystander cells to subvert host responses.

Cytosolic DNA induces type I interferon via activation of STING; the immediate STING activator is produced by the recently identified DNA sensor cGAS and is shown here to be an unorthodox cyclic dinucleotide harbouring a 2′-5′ linkage between guanosine and adenosine.

Cytosolic DNA arising from intracellular bacterial or viral infections induces type I interferon through activation of the DNA sensor cGAS, which catalyses the synthesis of cyclic dinucleotide which in turn activates STING; here the crystal structures of a carboxy-terminal fragment of cGAS alone and in complex with UTP and DNA–ATP–GTP complex are determined.

The cytoplasmic DNA receptor cGAS catalyses the synthesis of the second messenger cGAMP, which in turn activates type I interferon via STING; this study shows that cGAMP is transmitted to neighbouring cells via gap junction channels and activates STING, thus inducing an antiviral state in these bystander cells independent of paracrine interferon signalling.

In two recent reports in Science, James Chen and colleagues provide compelling evidence that detection of cytosolic DNA triggers the production of a novel second messenger, cyclic GMP-AMP (cGAMP), which in turn activates a signaling pathway that induces type I interferons (IFNs) in a STING-dependent manner. They further unravel a key role for a so far uncharacterized murine protein E330016A19 (human homolog: C6ORF150), now termed cGAMP synthetase (cGAS), to act as the DNA sensor that generates cGAMP.