positive regulation of cGAS/STING signaling pathway

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of of cGAS/STING signaling pathway. [PMID:37802025]

The cGAS/STING signaling pathway is a critical component of the innate immune response, primarily triggered by the presence of cytosolic DNA. This pathway plays a pivotal role in recognizing and responding to diverse threats, including viral and bacterial infections, as well as tumor cells. The positive regulation of this pathway involves a series of intricate steps that ensure an appropriate and robust immune response.

1. **DNA Sensing by cGAS:** The journey begins with the detection of cytosolic DNA by cyclic GMP-AMP synthase (cGAS). This sensor protein recognizes the presence of foreign DNA, such as viral or bacterial DNA, or even self-DNA that has escaped its normal nuclear compartmentalization. The recognition of DNA triggers cGAS to catalyze the synthesis of cyclic GMP-AMP (cGAMP), a second messenger molecule.

2. **cGAMP Binding to STING:** cGAMP, generated by cGAS, acts as a signaling molecule, diffusing to the endoplasmic reticulum (ER) membrane. It binds to the stimulator of interferon genes (STING) protein, a transmembrane receptor located on the ER. This binding event initiates a cascade of downstream signaling events.

3. **STING Activation and Oligomerization:** The binding of cGAMP to STING triggers a conformational change within STING, activating its signaling function. Activated STING undergoes oligomerization, forming dimers or higher-order oligomers.

4. **TBK1 Recruitment and Activation:** This oligomerized STING complex then recruits and activates TANK-binding kinase 1 (TBK1), a key kinase involved in downstream signaling. TBK1 is recruited to the STING complex via a direct interaction between their respective domains.

5. **IRF3 Phosphorylation:** The activated TBK1 phosphorylates interferon regulatory factor 3 (IRF3), a transcription factor that plays a crucial role in the induction of type I interferons (IFNs). Phosphorylation of IRF3 promotes its dimerization and nuclear translocation.

6. **IFN Production and Immune Response:** The dimerized, phosphorylated IRF3 translocates to the nucleus, where it binds to specific DNA sequences known as interferon-stimulated response elements (ISREs). This binding event leads to the transcription and production of type I IFNs, such as IFN-α and IFN-β.

7. **Antiviral and Antibacterial Effects:** Type I IFNs act as potent antiviral and antibacterial agents. They induce a wide range of antiviral and antibacterial responses, including the upregulation of antiviral genes, the inhibition of viral replication, and the activation of immune cells.

8. **Positive Regulation:** The positive regulation of the cGAS/STING pathway can be influenced by several factors, including:
* **Activation of upstream signaling:** The activation of other immune pathways can enhance the cGAS/STING response. For example, the activation of toll-like receptors (TLRs) can augment the production of IFN-β by enhancing cGAS activation.
* **Post-translational modifications:** Modifications of cGAS and STING, such as phosphorylation, can alter their activity and enhance their ability to trigger signaling.
* **Protein-protein interactions:** Interactions with other proteins, such as adaptor molecules, can modulate the signaling complex formation and downstream signaling events.

9. **Feedback Regulation:** There are also negative regulatory mechanisms that dampen the cGAS/STING pathway to prevent excessive inflammation and immune activation. These mechanisms include dephosphorylation of IRF3, ubiquitination of STING, and the expression of inhibitors of the pathway.

In summary, the positive regulation of the cGAS/STING signaling pathway is a tightly regulated process that involves a cascade of molecular events, starting with DNA sensing by cGAS, followed by activation of STING, TBK1, and IRF3, culminating in the production of type I IFNs, ultimately contributing to a robust innate immune response.'
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Proteins (2)

Compounds (8)