cGAS–STING-Pathway

cGAS (cyclic GMP-AMP synthase) is a cytosolic DNA sensor that recognizes cytosolic DNA. Normally, DNA is only found in the cell nucleus or in mitochondria. Foreign or misplaced DNA in the cytosol is recognized as a threat to cellular integrity. cGAS binds to this cytosolic double-stranded DNA (dsDNA) - independent of sequence, but dependent on length (>40 bp particularly efficiently).

Synthesis of the second messenger "cGAMP": After binding to DNA, cGAS becomes enzymatically active. It catalyzes the formation of cyclic GMP-AMP (cGAMP) from GTP and ATP. cGAMP is a cyclic dinucleotide and serves as a second messenger.

The cGAS-STING signaling pathway not only has an antiviral function. It also plays a role in:

• Autoimmunity (e.g. Aicardi-Goutières syndrome)
• tumor immunity and in
• UV-induced DNA damage response

Activation of STING: cGAMP binds to STING (STING = Stimulator of Interferon Genes). STING is an adapter protein in the endoplasmic reticulum (ER) (Burdette DL et al. 2011). This binding leads to a conformational change of the STING protein and to its activation. Activated STING translocates from the endoplasmic reticulum via the Golgi apparatus into the perinuclear region.

Signal transduction (phosphorylation cascade): In the Golgi apparatus, STING recruits the kinase TBK1 (TANK-binding kinase 1). Activated TBK1 phosphorylates STING and the transcription factor IRF3 (Interferon Regulatory Factor 3). The now phosphorylated IRF3 protein dimerizes, translocates into the cell nucleus and activates the transcription of type I interferons (IFN-beta, IFN-alpha). A very strong STING signal can also trigger apoptosis of the cell (Ishikawa H et al. 2008).

Immune response: Type I interferons are secreted and bind to IFNAR receptors on neighboring cells. This triggers a Jak-STAT signaling cascade, which results in the expression of numerous ISGs(interferon-stimulated genes). These genes or their gene products strengthen the antiviral defense, promote apoptosis and antigen presentation.

STING can also activate NF-kappaB, which releases inflammatory cytokines such as interleukin-6 or TNF-alpha.

1. Burdette DL et al. (2011) STING is a direct innate immune sensor of cyclic di-GMP. Nature 478(7370):515-518.
2. David C et al. (2022) Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI). Cells 11:318.
3. Domizio JD et al. (2022) The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature 603(7899):145-151.
4. Ferguson PJ (2008) Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype. Arthritis Rheum 58: 3264-3269
5. Frémond ML et al.(2021) Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients. J Allergy Clin Immunol Pract. 9: 803-818.
6. Ishikawa H et al. (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling. Nature 455(7213):674-678