Human cGAS Dual Reporter HEK293 Cells

Cyclic GMP-AMP synthase, also known as cGAS or cGAMP synthase, is the primary sensor of cytosolic double-stranded DNA (dsDNA), a danger signal indicating possible disturbances in homeostasis caused by infection, sterile tissue damage, or cancer [1]. It triggers innate immune responses through the production of type I interferons (IFNs) [2]. 

In response to cytosolic dsDNA (e.g., microbial DNA, mitochondrial DNA, extracellular self-DNA), cGAS catalyzes its substrates GTP and ATP (guanosine triphosphate and adenosine triphosphate [ATP]) into  the cyclic dinucleotide (CDN) 2’3’-cGAMP. CDNs bind directly to the stimulator of interferon genes (STING), leading to TBK1‑IRF3-mediated activation of IFN-stimulated response elements (ISRE) in the promoters of IFN-stimulated genes (ISG) [1,3,4].

Current research on the cGAS-STING pathway is focusing on finding new cancer therapies, considering its role in inducing cell-intrinsic processes, such as autophagy, cellular senescence, and cell death. In contrast, dysregulated or excessive activation of the cGAS-STING pathway can cause primary pathogenesis and the manifestation of several autoimmune diseases; thus, identifying compounds, delivery pathways, and treatment regimens targeting the suppression of the cGAS-STING pathway can provide novel approaches to alleviate the symptoms of autoimmune disorders or inflammation [1].

References:

1. Zhou J, et al., 2023. Significance of the cGAS-STING Pathway in Health and Disease. Int J Mol Sci. 24(17):13316.
2. Sun L. et al., 2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339(6121):786-91.
3. Gao P. et al., 2013. Cyclic [G(2’,5’)pA(3’,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 153(5):1094-107.
4. Ablasser A. et al., 2013. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature. 498(7454):380-4.
5. Lama L, et al. 2019. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. Nat Commun.10(1):2261.