Structural basis for CGAS sequencing and homophobia by chromatin

cGAS (cyclic GMP-AMP synthase) is an innate immune sensor for cytosolic microbial DNA1. Upon binding to DNA, it synthesizes the messenger cGAMP (2’3 ‘cyclic GMP-AMP)2-4, Which triggers the production of cell-autonomous defense and type of interferences and pro-inflammatory cytokines through activation of STING5. In addition to responding to cytosolic microbial DNA, CGAS also recognizes mis-localized cytosolic self-DNA and is implicated in autoimmunity and sterile inflammation6.7. Specificity to DNA associated with pathogen or damage was thought to be due to cytosolic fusion. However, recent findings strongly place cGAS in the nucleus.8-10, Where tight chromatin tethering is also important for self-DNA to prevent autoreactivity8. Here we show how CGAS is irrigated and inhibited by chromatin. We provide 3.1 o cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleus, suggesting that cGAS does not interact with nucleosomal DNA, but rather histone 2A / 2B, where it is tightly bound to the “acidic patch” is. . The interaction burys the cGAS ‘DNA binding site B, blocking the formation of the active cGAS dimer. Acidic patch binding strengthens agonistic DNA, suggesting that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as an actively transferred genomic region. Overall, our work shows how nuclear cGAS is sequenced by chromatin and provides a mechanism for nuclear self-DNA to inhibit autoreactivity.

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