by The cGAS-STING Pathway plays a crucial role in host defense against cytoplasmic DNA from invading pathogens. When double-stranded DNA is present in the cytoplasm, which is not normal, it activates the enzyme cyclic GMP-AMP synthase or cGAS. cGAS acts as a DNA sensor that detects cytosolic DNA and produces the second messenger cyclic GMP-AMP (cGAMP) from GTP and ATP.
cGAMP then binds and activates the endoplasmic reticulum-anchored protein stimulator of interferon genes or cGAS-STING Pathway. Once activated, STING triggers a signaling cascade that induces type I interferons (IFNs) and proinflammatory cytokines expression via the transcription factors IRF3 and NF-κB. These IFNs and cytokines recruit and activate innate and adaptive immune cells to clear the invading pathogen.
Signaling Through STING
Upon binding to cGAMP, STING undergoes conformational changes that allow it to interact and activate tank-binding kinase 1 (TBK1). TBK1 then phosphorylates and activates the transcription factors interferon regulatory factor 3 (IRF3) and NF- κB essential modulator (NEMO). Phosphorylated IRF3 forms homo- or heterodimers that translocate into the nucleus and induce the expression of type I IFNs and various proinflammatory cytokines.
Phosphorylated NEMO activates the IKK complex that mediates NF- κB signaling. NF- κB enters the nucleus and triggers transcription of various cytokines involved in host defense. The production of type I IFNs and cytokines orchestrates both the innate and adaptive immune responses against intracellular pathogens and tumors.
Regulation
Given its critical role in host defense, it is tightly regulated at multiple levels to prevent excessive and uncontrolled immune activation. Cyclic dinucleotides produced by cGAS are quickly degraded by DNA exonucleases to terminate signaling. The E3 ligase TRIM56 ubiquitinates and degrades cGAS upon DNA clearance from the cytoplasm.
Additionally, STING is regulated by phosphorylation and ubiquitination. The protein tyrosine phosphatase PTPN2 and ubiquitin ligase RNF5 tag STING for proteasomal degradation, thereby terminating its signal. STING signaling is also negatively regulated by the deubiquitinase CYLD which removes K63-linked ubiquitin chains from STING. Proper regulation of the cGAS-STING Pathway through feedback mechanisms is crucial for mounting efficient immune responses without inducing autoinflammation.
Role Of cGAS STING In Antiviral Immunity And Cancer Immunotherapy
Given its critical role in cytosolic DNA sensing, the cGAS-STING Pathway acts as a major sensor of viral and tumor DNA in the cytoplasm. Viruses like herpesviruses that replicate in the cytosol are strongly sensed through cGAS-STING signaling. Activation of this pathway by viral DNA triggers potent type I IFN responses and recruitment of adaptive immunity against various DNA and RNA viruses.
Similarly, tumor cells may release mitochondrial or genomic DNA into the cytoplasm due to cellular stress or damage. This cytosolic tumor DNA activates the cGAS-STING Pathway leading to IFN responses and priming of anti-tumor immunity. Drugs targeting STING have shown remarkable efficacy in enhancing responses to immunotherapy in various cancers. Ongoing research seeks to fully leverage the cGAS-STING Pathway for developing novel antiviral and cancer therapeutic strategies.
The cGAS-STING Pathway acts as a key cytosolic DNA sensor that triggers potent type I interferon production and inflammatory responses upon sensing cytoplasmic DNA. Precise regulation of this pathway through feedback controls prevents excessive inflammation. Targeting this pathway holds promise for developing new immunotherapies against viral infections and cancers. Continued research will provide deeper insights into modulating cGAS-STING signaling for clinical benefit.
*Note:
1. Source: Coherent Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author - Alice Mutum
Alice Mutum is a seasoned senior content editor at Coherent Market Insights, leveraging extensive expertise gained from her previous role as a content writer. With seven years in content development, Alice masterfully employs SEO best practices and cutting-edge digital marketing strategies to craft high-ranking, impactful content. As an editor, she meticulously ensures flawless grammar and punctuation, precise data accuracy, and perfect alignment with audience needs in every research report. Alice's dedication to excellence and her strategic approach to content make her an invaluable asset in the world of market insights. LinkedIn
