the cGAS-StinG pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDnA from incoming viruses, bacteria, or self. cYcLic GMp-AMp SYntHASe (cGAS) is the sensor protein that directly binds dsDnAs. cGAS synthesizes cyclic GMp-AMp (cGAMp), which binds to the adaptor StiMULAtoR of inteRfeRon GeneS (StinG), activating an inteRfeRon ReGULAtoRY FACTOR 3 (IRF3)-mediated immune response. Constitutive activation can result in interferonopathies such as Aicardi-Goutieres Syndrome (AGS) or other lupus-like autoimmune disorders. While inhibitors targeting mouse or human cGAS have been reported, the identification of a small molecule that targets both homologs of cGAS has been challenging. Here, we show that RU.521 is capable of potently and selectively inhibiting mouse and human cGAS in cell lines and human primary cells. this inhibitory activity requires the presence of cGAS, but it cannot suppress an immune response in cells activated by RNA, Toll-like receptor ligands, cGAMP, or recombinant interferon. Importantly, when RU.521 is applied to cells, the production of dsDnA-induced intracellular cGAMp is suppressed in a dose-dependent manner. Our work validates the use of RU.521 for probing DNA-induced innate immune responses and underscores its potential as an ideal scaffold towards pre-clinical development, given its potency against human and mouse cGAS. The deployment of pattern recognition receptors (PRRs) is the primary method for the innate immune system to detect pathogens or cellular damage via their associated molecular patterns (PAMPs and DAMPs) 1. Among PRRs are cytoplasmic RNA and DNA nucleic acid sensors 2-9. Nucleic acids from incoming pathogens have distinct molecular features that are recognized by host PRRs localized within the cytosol 10. Human CYCLIC GMP-AMP SYNTHASE (h-cGAS) 11,12 produces the cyclic dinucleotide c[G(2′,5′)pA(3′,5′)p], or cGAMP, upon binding cytoplasmic dsDNA 13-15. cGAMP then binds to the endoplasmic reticulum-bound adaptor protein STIMULATOR OF INTERFERON GENES (STING), and induces a signaling cascade that ultimately results in the phosphorylation, dimerization, and translocation of INTERFERON REGULATORY FACTOR 3 (IRF3) into the nucleus 16-18. The nuclear translocation of activated IRF3 leads to the transcriptional upregulation of type I interferons and pro-inflammatory cytokines 2,19,20. An essential role for cGAS is its capacity to detect DNA derived from invading pathogens. Numerous reports have demonstrated the role of cGAS against prokaryotes including L. monocytogenes 21 , C. trachomatis 22 , L. pneumophila 23 , and M. tuberculosis 24,25. Moreover, cGAS has also been reported to detect DNA derived from viruses 26. Upon infection, the cGAS-STING pathway is activated by viruses, including some members of the herpes family 27 , oncogenic viruses like HPV 28 , and even retroviruses such as HIV 29. By serving as the first line of defense against a diverse body of pathogenic DNAs, cGAS establishes its necessity to the cell's innate immune system. The proper re...
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