The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human STING

Diner, Elie J.; Burdette, Dara; Wilson, Susan C.; Monroe, Kathryn M.; Kellenberger, Colleen A.; Hyodo, Mamoru; Hayakawa, Yoshihiro; Hammond, Ming C.; Vance, Russell E.

doi:10.1016/j.celrep.2013.05.009

Cited by 629 publications

(607 citation statements)

References 29 publications

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“…The IFNβ-luciferase reporter plasmid was a kind give of R. Vance 34 . Using Gibson assembly the luciferase reporter gene was swapped with eGFP (from pBABE-H2B described above) to form the IFNβ-GFP cassette.…”

Section: Methodsmentioning

confidence: 99%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

1,096

780

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Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumor microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumor responses to radiotherapy1. An enigmatic feature of this phenomenon is its delayed onset (days), in contrast to the acute DNA damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate limiting steps that are essential for DNA-damage induced inflammation. Here, we show that cell cycle progression through mitosis following DNA double-strand breaks (DSBs) leads to the formation of micronuclei, which precede activation of inflammatory signaling and are a repository for the pattern recognition receptor cGAS. Inhibiting progression through mitosis or loss of pattern recognition by cGAS-STING impaired interferon signaling. Moreover, STING loss prevented the regression of abscopal tumors in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

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Section: Methodsmentioning

confidence: 99%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

1,096

780

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“…1A), have been discovered in bacteria (7,8). Furthermore, an isomer of cAG containing a noncanonical 2′-5′ phosphodiester linkage (2′,3′-cGAMP) has been found to be produced in response to cytosolic DNA in mammalian cells (9)(10)(11)(12). The mammalian sensor STING is stimulated by both bacterial cyclic dinucleotides and 2′,3′-cGAMP to activate the innate immune response (13).…”

mentioning

confidence: 99%

GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP

Kellenberger¹,

Wilson²,

Hickey³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

146

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Cyclic dinucleotides are an expanding class of signaling molecules that control many aspects of bacterial physiology. A synthase for cyclic AMP-GMP (cAG, also referenced as 3′-5′, 3′-5′ cGAMP) called DncV is associated with hyperinfectivity of Vibrio cholerae but has not been found in many bacteria, raising questions about the prevalence and function of cAG signaling. We have discovered that the environmental bacterium Geobacter sulfurreducens produces cAG and uses a subset of GEMM-I class riboswitches (GEMM-Ib, Genes for the Environment, Membranes, and Motility) as specific receptors for cAG. GEMM-Ib riboswitches regulate genes associated with extracellular electron transfer; thus cAG signaling may control aspects of bacterial electrophysiology. These findings expand the role of cAG beyond organisms that harbor DncV and beyond pathogenesis to microbial geochemistry, which is important to environmental remediation and microbial fuel cell development. Finally, we have developed an RNA-based fluorescent biosensor for live-cell imaging of cAG. This selective, genetically encodable biosensor will be useful to probe the biochemistry and cell biology of cAG signaling in diverse bacteria.

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“…Following binding to dsDNA, cGAS undergoes a conformational change, revealing a catalytic active site that synthesizes the cyclic dinucleotide, cyclic dinucleotide GMP-AMP (cGAMP) (14). cGAMP binds to the adapter protein, stimulator of IFN genes (STING), which triggers activation of TANK-binding kinase 1 and phosphorylation of IFN regulatory factor 3, with resulting transcription of IFN-b (12,15).…”

mentioning

confidence: 99%

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

Woodward

Sasaki

et al. 2015

The Journal of Immunology

175

171

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Type I IFN is strongly implicated in the pathogenesis of systemic autoimmune diseases, such as lupus, and rare monogenic IFNopathies, including Aicardi–Goutières syndrome. Recently, a new DNA-activated pathway involving the enzyme cyclic GMP-AMP synthase (cGAS) was described and potentially linked to Aicardi–Goutières syndrome. To identify drugs that could potentially inhibit cGAS activity, we performed in silico screening of drug libraries. By computational analysis, we identified several antimalarial drugs (AMDs) that were predicted to interact with the cGAS/dsDNA complex. Our studies validated that several AMDs were effective inhibitors of IFN-β production and that they functioned by inhibiting dsDNA stimulation of cGAS. Because AMDs have been widely used in human diseases and have an excellent safety profile, our findings suggest new therapeutic strategies for the treatment of severe debilitating diseases associated with type I IFNs due to cGAS activation.

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The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human STING

Cited by 629 publications

References 29 publications

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Mitotic progression following DNA damage enables pattern recognition within micronuclei

GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

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