Cyclic GMP-AMP Signaling in Innate Immune Response

The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) axis constitutes a central pathway in the detection of cytosolic DNA and the initiation of innate immune programmes. Upon binding double-stranded DNA from pathogens, damaged nuclei or mitochondria, cGAS catalyses the formation of the cyclic dinucleotide second messenger cyclic GMP-AMP (cGAMP). cGAMP binds to and induces conformational activation of STING, an endoplasmic reticulum-resident adaptor that relocates to the Golgi and triggers downstream kinase cascades. These events culminate in the production of type I interferons and pro-inflammatory cytokines through activation of transcription factors such as IRF3 and NF-κB. Beyond antiviral defence, cGAS–STING signalling influences cellular senescence, neuroinflammation, vascular tone and tumour immunity, acting through both autocrine and paracrine mechanisms. The pathway is subject to multilayered regulation, including lipid modifications of STING, ubiquitin-mediated control of adaptor proteins and cell-type specific signal thresholds. Dysregulation underlies a spectrum of chronic inflammatory disorders, neurodegenerative diseases and cardiovascular dysfunction, making cGAMP signalling a prime target for therapeutic modulation.

Research from Nature Portfolio

Recent studies have shown that sustained activation of the cGAS–STING pathway drives persistent inflammation during ageing. In aged murine models, inhibition of STING reduced systemic inflammatory markers, preserved tissue function and improved cognitive performance by limiting microglial activation. Structural insights have identified palmitoylation of STING at the Golgi as essential for its clustering and signal propagation; pharmacological blockade of this lipid modification abolishes type I interferon induction. Investigations into the amplitude of STING signalling reveal that T lymphocytes exhibit an exaggerated STING response, which, when surpassing a critical threshold, induces pro-apoptotic programmes. These findings highlight palmitoylation and signal strength as key regulatory nodes that determine both the magnitude and the cellular outcome of cGAMP-driven innate immunity.

Cyclic GMP-AMP Signaling in Innate Immune Response publication trend

The graph below shows the total number of articles in cyclic gmp-amp signaling in innate immune response across all publications each year (not limited to Nature Index journals).

Technical terms

cGAS (cyclic GMP-AMP synthase): Enzyme that recognises cytosolic DNA and produces the second messenger cGAMP.

cGAMP (cyclic GMP-AMP): Cyclic dinucleotide that binds to and activates STING, initiating immune signalling.

STING (stimulator of interferon genes): Adaptor protein that transduces cGAMP binding into type I interferon and cytokine responses.

Palmitoylation: Reversible lipid modification attaching palmitic acid to proteins, regulating STING localisation and activation.

mPTP (mitochondrial permeability transition pore): Channel whose opening releases mitochondrial DNA, triggering cGAS activation.

PKGI (cGMP-dependent protein kinase I): Kinase activated by cyclic nucleotides that mediates vascular smooth muscle relaxation.

NF-κB (nuclear factor κB): Transcription factor central to induction of inflammatory gene expression.

IFI16: Nuclear DNA sensor that can engage STING in a cGAS-independent manner following genotoxic stress.

References

1. cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature (2023).
2. Sensing Cytosolic DNA Lowers Blood Pressure by Direct cGAMP-Dependent PKGI Activation. Circulation (2023).
3. Activation of STING requires palmitoylation at the Golgi. Nature Communications (2016).
4. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell (2020).
5. Signalling strength determines proapoptotic functions of STING. Nature Communications (2017).
6. Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage. Molecular Cell (2018).