All cells in the human body have evolved sophisticated innate immune sensing mechanisms to detect the presence of pathogens. These include pattern recognition receptors that can identify pathogen associated molecular patterns expressed by bacteria, viruses and other microbes. Two key families of receptors involved in pathogen recognition are the Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). TLRs such as TLR3, TLR7 and TLR9 are expressed on the cell surface and in endosomes where they can detect nucleic acids from pathogens that have been endocytosed. RLRs like RIG-I and MDA5 are cytosolic sensors that detect viral RNA.
Discovery Of The cGAS STING Pathway
In addition to detecting pathogen nucleic acids within endosomes or in the cytosol of infected cells, the innate immune system also needs to sense DNA or RNA that is aberrantly present within the cytosol. This could occur as a result of viral infection or due to cellular damage that leads to leakage of nuclear or mitochondrial DNA into the cytoplasm. In 2011, independent studies led to the discovery of the cGAS-STING Pathway which senses cytoplasmic DNA and triggers type I interferon production. The studies identified the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase) and showed it binds DNA and generates the second messenger cyclic GAMP (cGAMP). cGAMP then goes on to bind and activate the endoplasmic reticulum-associated molecule STING (stimulator of interferon genes), triggering a signaling cascade that induces type I interferon expression.
Mechanism Of The cGAS STING Pathway
When double stranded DNA is present in the cytoplasm, it is bound and engaged by cGAS. cGAS possesses enzymatic activity and undergoes a conformational change when bound to DNA which allows it to synthesize the novel cyclic dinucleotide cGAMP from ATP and GTP. cGAMP acts as a second messenger and diffuses through the cell to engage and activate STING on the membrane of the endoplasmic reticulum. STING undergoes phosphorylation and a conformational change upon ligation by cGAMP. This leads to recruitment and activation of the kinase TBK1 which in turn phosphorylates and activates the transcription factors IRF3 and NF-κB. IRF3 and NF-κB then dimerize and translocate to the nucleus to drive expression of Type I interferon genes including IFN-β as well as numerous pro-inflammatory cytokine genes. The secreted interferons act in an autocrine and paracrine manner by engaging the interferon alpha/beta receptor (IFNAR) and activating the JAK-STAT signaling cascade to induce hundreds of interferon stimulated genes which establish an antiviral state in the cell and recruit components of the adaptive immune system.
Cell Types That Utilize The cGAS STING Pathway
The pathway for sensing of cytoplasmic DNA and triggering of type I interferons is utilized across many cell types in the body. It plays an important role in dendritic cells, macrophages and fibroblasts for the detection of viral and bacterial DNA during infection. It is also critical in endothelial cells lining blood vessels. When these cells are exposed to cytomegalovirus or HIV, they can detect abortive infection through them. Neutrophils and monocytes also rely on cGAS STING signaling to detect bacterial and fungal DNA. Additionally, the pathway acts as a major DNA sensor in most nucleated cell types within tissues and organs. This includes sensing of self DNA that leaks into the cytoplasm following cellular stress or necrosis during sterile inflammation. Therefore, cGAS STING represents a central and ubiquitous system for detection of aberrant DNA throughout the body.
Role In Anti-Tumor Immunity And Immunotherapy
As cancer cells are vulnerable to immune detection, they also plays an important role in anti-tumor surveillance and immunity. Many malignant cells actively shed DNA fragments known as tumor-derived DNA into the cytoplasm of neighboring stromal fibroblasts and immune cells. This tumor DNA engages the cGAS STING pathway to stimulate interferon signaling and boost anti-tumoral immune responses. Therefore, loss of either cGAS or STING expression can impair the immune system's ability to detect and eliminate developing tumors. Studies have also shown that systemic administration of STING activators like cGAMP can induce robust T cell mediated anti-tumor effects against a variety of established malignancies through the induction of CD8+ T cell priming. Based on these properties, targeting and stimulating they has emerged as a promising strategy for cancer immunotherapy.
Role In Autoimmune Disease Development
While the cGAS STING pathway plays an important role in defending the host against infections, excessive or dysfunctional activation can also drive inflammatory and autoimmune pathology. Many autoimmune disorders stem from a loss of tolerance to self, resulting in the generation of auto-reactive T cells and autoantibodies against an individual's own tissues. Numerous studies have implicated over-stimulation of cGAS STING signaling through endogenous sources of self DNA as a potential trigger for various autoimmune conditions like systemic lupus erythematosus and Aicardi-Goutières syndrome. Elevated IFN levels and elevated markers of it activation are commonly observed in affected patients. Polymorphisms in STING that enhance its sensitivity have also been linked to increased autoimmunity risk. Thus, maintaining a fine balance in cGAS STING activity appears crucial for avoiding autoimmune pathogenesis.
The cGAS STING pathway forms a central component of the cytosolic DNA sensing system that triggers robust innate immune activation through type I interferon responses. It plays an indispensable role across multiple cell types in defending against a wide range.
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*Note:
1. Source: Coherent Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it