The Innate Immune Response Initiated By The Cgas-sting Pathway

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Cyclic GMP-AMP synthase, also known as cGAS, is a key cytosolic DNA sensor that plays a critical role in initiating the innate immune response against foreign DNA. cGAS was originally identified through its ability to synthesize the novel cyclic dinucleotide cGMP-AMP (cGAMP) in the presence of double-stranded DNA (dsDNA). This occurs when dsDNA from invading pathogens such as viruses or bacteria infiltrates the cytosol after escaping from intracellular vesicles. cGAS has two domains - an N-terminal catalytic domain that binds ATP/GTP to synthesize cGAMP, and a C-terminal DNA-binding domain that allows it to detect cytosolic dsDNA. Once produced, cGAMP acts as a second messenger that triggers downstream signaling events through stimulation of the stimulator of interferon genes (STING) protein.

STING: The Adaptor Protein That Triggers Type I Interferon Response

STING, also known as MITA, ERIS or MPYS, is an endoplasmic reticulum-localized adaptor protein that plays a pivotal role in bridging cytosolic DNA sensing by cGAS to downstream effector responses. Upon binding to cGAMP, STING undergoes a conformational change ...
... that allows it to oligomerize and translocate to specialized puncta on the cytoplasmic side of the ER membrane. Here, cGAS-STING Pathway recruits and activates the TBK1 kinase, which in turn phosphorylates and activates the interferon regulatory factor 3 (IRF3) transcription factor. Phosphorylated IRF3 then translocates to the nucleus where it induces expression of type I interferon (IFN) genes, most notably IFN-β. Secreted IFN-β engages the IFNα/β receptor on neighboring cells in both paracrine and autocrine manner to transcriptionally upregulate over 300 interferon-stimulated genes (ISGs) that establish an antiviral state.

Downstream Effector Pathways Triggered By STING

In addition to driving type I IFN expression, STING is able to signal through several other downstream effector mechanisms to potentiate the antiviral response. Upon relocalization to ER membranes, STING activates the NF-κB transcription factor through recruitment of the IKK kinase complex. NF-κB then translocates to the nucleus to induce expression of proinflammatory cytokines like IL-6 and chemokines that help recruit immune cells to sites of infection. STING signaling also culminates in activation of the MAPK pathway through recruitment of the BATF3 transcription factor. BATF3 drives production of a diverse array of defensive effector molecules. Lastly, recent studies indicate STING may promote autophagy through interaction with Beclin-1, contributing to clearance of invading pathogens. These downstream pathways collectively enhance intracellular pathogen detection and orchestrate a multilayered defense program.

Regulation

Tight regulation of the cGAS-STING Pathway is indispensable to avoid excessive or prolonged inflammation that could prove detrimental to the host. Cells have evolved multiple mechanisms to control cGAS-STING signaling at different levels. For instance, endogenous self DNA in the cytosol is marked by 5-hydroxymethylation to prevent erroneous activation of cGAS. DNA modifications like methylation also influence cGAS binding affinity. Cleavage and degradation of cGAMP by downstream nucleases like ENPP serve to dampen STING signaling. STING is subject to both K63-linked ubiquitination to promote downstream signaling, as well as K48-linked ubiquitination for proteasomal degradation to terminate the response. Additional pathways modulate STING trafficking and interaction with downstream effectors. Precise control over the amplitude and duration of cGAS-STING Pathway activation is crucial for maximizing pathogen control without harming the host.

Role Of cGAS-STING Sensing In Disease

Dysregulation of the cGAS-STING Pathway contributes to the pathogenesis of several inflammatory and autoimmune diseases. Aberrant cytoplasmic DNA accumulation has been linked to hyperactivation of STING in conditions like Aicardi-Goutieres syndrome, a Mendelian interferonopathy associated with mutations impairing intracellular DNA clearance enzymes. Autoantibodies targeting STING have also been found in patients with systemic lupus erythematosus and suggested to perpetuate inflammation. Conversely, defects in cGAS or STING predispose individuals to recurrent viral, fungal and bacterial infections due to impaired cytosolic DNA sensing. Given the central role of cGAS-STING Pathway in sensing invading nucleic acids, modulating the pathway responsiveness represents an attractive strategy for treatment of various immune-mediated or infectious diseases. Elucidating its complex regulation continues to inspire novel therapeutic opportunities.

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Author Bio:
Alice Mutum is a seasoned senior content editor at Coherent 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 ing 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 insights. (LinkedIn: www.linkedin.com/in/alice-mutum-3b247b137 )
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1. Source: Coherent Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it