Advances in Life Science and Biotechnology

Opinion - (2023) Volume 11, Issue 1

Molecular processes and cellular activities of cGAS-STING signaling
Sherwood Roger*
Department of Neurology, University of Wurzburg, Wurzburg, Germany
*Correspondence: Sherwood Roger, Department of Neurology, University of Wurzburg, Wurzburg, Germany,

Received: 30-Mar-2023, Manuscript No. ALSB-23-93600; Editor assigned: 03-Apr-2023, Pre QC No. ALSB-23-93600 (PQ); Reviewed: 17-Apr-2023, QC No. ALSB-23-93600; Revised: 29-May-2023, Manuscript No. ALSB-23-93600 (R); Published: 05-Jun-2023, DOI: 10.51268/2736-1837.23.11.083


The detection of pathogenic DNA by the cGAS-STING signaling axis, which consists of the cyclic GMP-AMP synthase (cGAS) and the cyclic GMP-AMP receptor Stimulator of Interferon Genes (STING), leads in a potent type I interferon response to bacteriological infections. However, it should be noted that in addition to sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including DNA released from mitochondria and extra nuclear chromatin caused by genotoxic stress. In autoimmunity, sterile inflammatory responses, and cellular senescence, cGAS-STING becomes a crucial axis. Initially, it was believed that the co-localization of cGAS and DNA in the cytosol defined the specificity of the pathway for non-self. However, it has since been discovered that cGAS is also present in the nucleus and at the plasma membrane, and that this subcellular compartmentalization is connected to the signaling specificity of cGAS. Both cGAS and STING were found to have additional activities, independent of the interferon response, further confounding the cGAS-STING signaling as a response mechanism to infectious pathogens. They include controlling DNA repair, signaling STING to NF-B and MAPK, inducing autophagy, and lysosome-dependent cell death, among other non-catalytic functions of cGAS.

The identification and defense systems of cells against foreign genetic material are an ancient and fundamental aspect of living systems. Pattern Recognition Receptors (PRRs) that are genetically encoded recognize different pathogen and damage related chemical patterns (PAMPs and DAMPs). In addition to the onset of cell autonomous defense mechanisms, their activation triggers the creation of soluble mediators like type I interferons and pro-inflammatory cytokines. As type I interferons are essential for preventing viral spread, PRRs that have evolved to detect viral infection often control how much of them are produced. Type I interferons disseminate antiviral immunity and activate the adaptive immune system in addition to boosting cell autonomous defense mechanisms in an autocrine way by increasing the production of interferon stimulated genes. An effective stimulator of a type I interferon response is cytosolic DNA.


DNA is typically restricted to the nucleus and mitochondria, where it is quickly broken down by nucleases in the cytosol and end lysosomal compartments. The cGAS-STING axis is activated by extracellular, mitochondrial, and nuclear DNA that enters the cytosol in addition to non-self DNA from sources such DNA viruses, retroviruses, intracellular bacteria, and protozoa. High cytosolic DNA levels can result in constitutive and systemic activation of cGAS-STING, which causes persistent inflammation. These conditions include malignancies, radiation therapy, cellular senescence, and autoimmune diseases including aicardi-goutieres syndrome and systemic lupus erythematosus. Hence, knowing the molecular and cellular specifics of cGAS-STING signaling is of pathology significant biomedical value. For the treatment of autoimmune and inflammatory illnesses, as well as to activate the innate immune system in immunological-silent (or "cold") tumours to elicit antitumor immunity, significant efforts are being made to create cGAS and STING inhibitors and activators.

Functions of cGAS

The primary enzymatic activity of cGAS is the production of cGAMP for STING activation. In order to induce antiviral and pro-inflammatory immune responses, STING activation then stimulates IRF3 and NF-B. At the same time, it also activates effector activities that are unrelated to gene expression. cGAMP can also activate antiviral responses in bystander cells. It can incorporate into viral capsids to infiltrate distant cells or diffuse through gap junctions to neighboring cells. Extracellular cGAMP can reach other cells by methods that are most likely channel-dependent when some cGAMP is released into the microenvironment.

Non-catalytic functions

It has been discovered that cGAS prevents DNA double strand breaks from being repaired by homologous recombination in the nucleus by a mechanism independent of STING or the catalytic activity of cGAS37. The DNA ends are cut into 3′ single strand tails for homologous recombination, where the RAD51 recombinase is loaded in a BRCA2 dependent manner. As the broken strand is stretched by DNA synthesis, strand pairing with the homologous template is catalyzed by RAD51. The nuclear localization of cGAS is influenced by active cGAS import, which is stimulated by the phosphorylation of Tyr215, as revealed in a preliminary investigation on the issue. The dephosphorylated Tyr215 is thought to be required for nuclear cGAS functions because it permits its appropriate connections with DNA. Tyr215 is positioned in a DNA binding region of cGAS, and the phosphomimetic Tyr215Glu mutation inhibits DNA binding.


The homologous dsDNA template and the cGAS produced oligomeric clusters in this instance, preventing the coupling of RAD51-DNA filaments and the penetration of the fragmented DNA strand into the homologous strand38. When cGAS was discovered to be chromatin associated throughout the cell cycle, it is likely that the delocalization of chromatin bound cGAS to sites of homologous recombination, where it competes with RAD51 for DNA, is what prevents homologous recombination from occurring, as opposed to the first hypothesis that it was just a result of nuclear import upon injury. Before the role of cGAS in homologous recombination was discovered, competitive interactions between proteins at recombination intermediates and cGAS had been discovered. It was then proposed that RAD51 and RPA sequester DNA fragments caused from DNA damage and restore in the nucleus to prevent cGAS activation.

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