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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.

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.

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.

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.

Toll-like receptors (TLRs) are an essential component of innate immunity. Here, the authors identify expression quantitative trait loci that are unique to TLR4-stimulation and highlight genes that may have a role in innate immune response.

On 24–27 September 2008, members of the scientific community gathered to discuss advances in innate immunity at the 'Toll meeting' in Cascais, Portugal. Before long, attendees noticed that 'Toll2008' might be a misnomer.

Neutrophils can release S100A8/S100A9 as an alarmin via gasdermin D pores. Here, the authors untangle the regulatory mechanisms driving this pathway and show that active repair processes make these pores transient, which can prevent the usual lytic cell death.

The induction of type I interferon is a critical checkpoint in antiviral immunity. Toll-like receptor 2 can unexpectedly induce type I interferon in the subset of inflammatory monocytes during infection with vaccinia virus.

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 transcription factor Sox2 has an additional function in neutrophils, as a cytoplasmic sensor of DNA. Upon binding bacterial DNA, Sox2 initiates a signaling cascade dependent on the kinase TAK1 and adaptor TAB2 that culminates in the expression of genes encoding pro-inflammatory molecules.

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.

This Review describes how microbial or self DNA that enters the cytoplasm can be detected by various mechanisms and triggers a range of cellular responses. These include the induction of antiviral innate immune responses and inflammasome-dependent caspase-1 activation and pyroptotic cell death.

The binding sites for the anticoagulant drug warfarin and for vitamin K on the human VKOR are determined through biochemistry and computational approaches. The results indicate a competitive mechanism of inhibition of VKOR by warfarin.

Pro-inflammatory signals trigger innate immune pathways with consequential metabolic remodeling. Here authors show that a rate-limiting enzymes of glycolysis, PFKL, is directly regulated by innate stimuli via phosphorylation at Ser775, which modification in turn influences pro-inflammatory cytokine production.

Toll-like receptors can initiate an immune response when they detect signs of a viral or microbial threat. New insight into how such receptor activation drives defence programs should aid our efforts to understand autoimmune diseases.

Production of mature interleukin 1β (IL-1β) requires Il1b transcription and inflammasome-mediated processing of IL-1β protein. Ruland and colleagues show that the RNA virus sensor RIG-I signals via the adaptors CARD9 and Asc to facilitate both processes.

Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

A reporter of caspase-1 activity based on Gaussia luciferase—iGLuc—reveals inflammasome activation in mouse cells and in vivo. iGLuc forms nonluminescent aggregates in cells that can be cleaved by specific proteases and, consequently, lead to luciferase activity. The design principle is applied to build reporters for several other proteases.

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 use of site-specific gene insertion is a powerful method for investigating gene function. Here the authors describe CRISPaint, a universal tagging system using CRISPR-Cas9 to insert genes in an NHEJ dependent manner.

N-acetylglucosamine kinase catalyses the phosphorylation of muramyl dipeptide and is thus essential for its recognition and immunostimulatory activity in human and mouse cells.

Activation of the NALP3 inflammasome induces interleukin 1β production and inflammation. Latz and colleagues show that silica uptake followed by lysosome disruption and cathepsin B release activates the NALP3 inflammasome.

This study describes sensing of circulating cell-free DNA after stroke as the mechanism leading to recurrent ischemic events.

High levels of neutralizing antibodies are successfully elicited against SARS-CoV-2 variants of concern, including omicron, after three exposures to the viral spike protein, mediated by vaccination with BNT162b2 alone or by a combination of vaccination and infection.

Biochemical and structural analyses show how tethering of the nucleotidyltransferase cGAS to chromatin prevents autoimmune recognition of nuclear DNA.

Stimulator of interferon genes (STING) is known to be involved in defence against DNA viruses, but its role in the control of RNA viruses remains poorly explored. Here the authors show that STING participates in an innate immune response to RNA virus infection in a cGAS-independent manner.

NLRP1 was the first inflammasome-forming sensor to be identified, but only recently has its mode of action been in the spotlight. Two groups now report cryo-EM structures demonstrating how NLRP1 is kept in check by the dipeptidyl peptidase DPP9, and they illuminate how DPP9 inhibition leads to NLRP1 inflammasome activation.

A nucleofection-based method to enable efficient gene editing of primary human resting CD4⁺ T cells.

Tumor necrosis factor (TNF) has various effects on phosphorylation-mediated cellular signaling. Combining phosphoproteomics, subcellular localization analyses and kinase inhibitor assays, the authors provide systems level insights into TNF signaling and identify modulators of TNF-induced cell death.

KMT9, a new histone lysine methyltransferase targeting H4K12, is enriched at promoters of genes encoding molecules involved in the cell cycle and controls the growth of androgen receptor–dependent and castration- and enzalutamide-resistant prostate cancer cells and xenograft tumors.

The lipopolysaccharide of the intracellular pathogen Shigella, in particular its O antigen, interacts with caspases and blocks their activation to prevent apoptosis.

Latz et al. review the molecular mechanisms that drive NLRP3 inflammasome activation and regulation, and discuss emerging targeting strategies.

The c-Jun transcription factor can mediate a cell's response to TNFa. Here, Riesenberg et al. show in melanoma cells that c-Jun has an inverse relationship with the key melanocyte transcription factor MITF and that high c-Jun levels contribute to melanoma heterogeneity and an inflammatory microenvironment.

siRNA is used to silence expression of a specific gene and, if modified by a triphosphate at the 5′ end, will also activate the helicase Rig-I, leading to interferon production. Poeck et al. now combine both of these activities in a single siRNA to kill melanoma cells by crippling a crucial tumor cell survival pathway and triggering an interferon-dependent antitumor immune response (pages 1152–1153).

A library of DNA constructs enables high-throughput, ligation-free production of transcription activator–like effector (TALE) genes for genetic engineering.

During atherosclerosis, crystals of cholesterol accumulate in atherosclerotic plaques. But are they a consequence or a cause of the inflammation associated with the disease? Here it is shown that small cholesterol crystals appear early in the development of atherosclerosis, and that they act as an endogenous danger signal, causing inflammation by activating the NLRP3 inflammasome pathway. Cholesterol crystals thus seem to be an early cause, rather than a late consequence, of inflammation.

Truncated reverse transcription of HIV RNA produces a single-stranded DNA intermediate with a unique Y-DNA stem-loop structure flanked by unpaired guanines. Schlee and colleagues show this Y-DNA activates cGAS to elicit the production of type I interferon.

The events leading to the inflammation and tissue damage associated with Alzheimer's disease are unclear. Golenbock and colleagues now show that amyloid-β activates the NALP3 inflammasome, which triggers the release of proinflammatory and neurotoxic factors.

The AIM2 inflammasome induces maturation of the proinflammatory cytokines IL-1β and IL-18. Using AIM2-deficient mice, Fitzgerald and colleagues and Alnemri and colleagues show that the AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.

This Review explains how innate sensors of DNA activate different types of programmed cell death. The authors consider the relevance of these cell death pathways during infection and in inflammatory diseases.

The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway senses DNA in the cytoplasm, whether of pathogenic or endogenous (chromatin or mitochondrial) origin, and triggers the interferon response. The mechanisms of DNA recognition and cGAS–STING activation and signalling are now coming into focus, providing insights into the cellular functions of this pathway, including interferon-independent roles.

A molecular mechanism for the sensitive detection of long and U-turn DNA by cyclic GMP–AMP synthase (cGAS) both in vitro and in human cells.

The therapeutic response of acute myeloid leukemia to the nucleoside analog Ara-C is controlled by SAMHD1, an enzyme that hydrolyzes the active metabolite Ara-CTP.