Abstract
Early detection of infectious nucleic acids released from invading pathogens by the innate immune system is critical for immune defense. Detection of these nucleic acids by host immune sensors and regulation of DNA sensing pathways have been significant interests in the past years. Here, current understandings of evolutionarily conserved DNA sensing cyclic GMP‐AMP (cGAMP) synthase (cGAS) are highlighted. Precise activation and tight regulation of cGAS are vital in appropriate innate immune responses, senescence, tumorigenesis and immunotherapy, and autoimmunity. Hence, substantial insights into cytosolic DNA sensing and immunotherapy of indispensable cytosolic sensors have been detailed to extend limited knowledge available thus far. This Review offers a critical, in‐depth understanding of cGAS regulation, cytosolic DNA sensing, and currently established therapeutic approaches of essential cytosolic immune agents for improved human health.
Highlights
CGAS-STING-mediated antiviral cellular response initiates downstream signaling pathways, which stimulate TANKThe innate immune system, armed with germline-encoded binding kinase 1 [TBK1, an IKK (IκB kinase)-related kinase].receptors called pattern-recognition receptors (PRRs), is on Subsequently, TBK1 plays a significant role in regulating the front line of defense to recognize infectious pathogen- innate immunity and activating type I interferon (IFN) reguassociated molecular patterns (PAMPs) of disease-causing latory factor 3 (IRF3).[6]
Www.advancedscience.com adjoining the primary DNA binding surface, and upon DNA binding for biochemical activation, shows switch-like conformational modifications. cGAS forms a 2:2 complex, which comprises dimeric cGAS, which interacts with two DNA molecules. It binds DNA predominantly by sequence-independent contacts in cooperation with phosphate-sugar backbone strands beside the minor groove (Figure 3A,B).[33a] biochemical and structural information propose that the regulation of humanspecific cGAS controls enzyme triggering by biasing cGAS– DNA contacts away from a marginal 2:2 complex and in the direction of higher-order protein–DNA oligomerization.[33b] the twofold DNA binding planes along with the protein–protein edge of cGAS are vital for activating IRF3, IFN-β induction, and target therapy for effective drug delivery.[33a]. Exclusively, DNA interacts with Zn thumb and spine
Ongoing studies have proven that genomic DNA harm or autophagy, cytosolic chromatin fragments (CCFs),[41] micronuclei, chromosomal instability,[42] and self-DNA escape could lead to pathophysiological outcomes, resulting in inflammatory reactions initiated by cGAS
Summary
CGAS-STING-mediated antiviral cellular response initiates downstream signaling pathways, which stimulate TANK. He received his Ph.D. degree in biochemistry and molecular biology at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/Peking Union Medical College in 2007 under the supervision of Professor Wang Linfang. Sox triggers the transforming growth factor beta-activated kinase 1 (TAK1) and its interacting partner TGFbeta activated kinase 1 (MAP3K7) binding protein 2 (TAB2), thereby activating the transcription factor NF-κB for innate immunity.[1] These cytosolic sensors and their innate immune pathways have become an immunotherapy target for the treatment of infectious diseases (Figure 2).[28]. Sensing microbial signatures triggers signaling pathways resulting in the initiation of transcription factors, comprising NF-κB and IRFs, inducing the production of IFNs, including pro-inflammatory cytokines.[29]. DNA-dependent RNA polymerase III (Pol III) senses cytosolic DNA and produces RNA, through detection of the subsequent RNA by RIG-I and the instigation of the downstream signaling pathways.[27]
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