Abstract
Cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) derived from invading pathogens and induces an interferon response via activation of the key downstream adaptor protein stimulator of interferon genes (STING). This is the most classic biological function of the cGAS-STING signaling pathway and is critical for preventing pathogenic microorganism invasion. In addition, cGAS can interact with various types of nucleic acids, including cDNA, DNA : RNA hybrids, and circular RNA, to contribute to a diverse set of biological functions. An increasing number of studies have revealed an important relationship between the cGAS-STING signaling pathway and autophagy, cellular senescence, antitumor immunity, inflammation, and autoimmune diseases. This review details the mechanism of action of cGAS as it interacts with different types of nucleic acids, its rich biological functions, and the potential for targeting this pathway to treat various diseases.
Highlights
In the 1980s, researchers already understood the correlation between bacterial DNA and immune activation in vitro [1], i.e., they knew that exposing macrophages to bacterial DNA could stimulate the expression of interferon-alpha (IFN-a) and interferon-beta (IFN-b), and induce the activation of natural killer cells and the release of interferon-gamma (IFN-g) [1, 2]
Further studies showed that the immune activation induced by bacterial DNA is related to its large number of unmethylated CpG motifs, which are different from the DNA motifs in humans and mice [3, 4]
Other pattern recognition receptors (PRRs) can recognize pathogen-derived nucleic acids and activate an immune response, activation of the Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an indispensable role in helping the host to resist pathogenic microorganism invasion
Summary
In the 1980s, researchers already understood the correlation between bacterial DNA and immune activation in vitro [1], i.e., they knew that exposing macrophages to bacterial DNA could stimulate the expression of interferon-alpha (IFN-a) and interferon-beta (IFN-b), and induce the activation of natural killer cells and the release of interferon-gamma (IFN-g) [1, 2]. Other PRRs can recognize pathogen-derived nucleic acids and activate an immune response, activation of the cGAS-STING signaling pathway plays an indispensable role in helping the host to resist pathogenic microorganism invasion. Genetic deletion of TFAM causes abnormal accumulation of mtDNA in the cytoplasm, leading to the activation of the cGAS-STING signaling pathway and production of IFN-I and ISGs [86].
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