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Publication Abstract from PubMed

cGAS (cyclic GMP-AMP synthase) is an innate immune sensor for cytosolic microbial DNA(1). Upon binding DNA, it synthesizes the messenger cGAMP (2'3' cyclic GMP-AMP)(2-4), which triggers cell-autonomous defense and the production of type I interferons and pro-inflammatory cytokines via activation of STING(5). Besides responding to cytosolic microbial DNA, cGAS also recognizes mis-localized cytosolic self-DNA and is implicated in autoimmunity and sterile inflammation(6,7). Specificity towards pathogen or damage associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus(8-10), where tight chromatin tethering is even important to prevent autoreactivity to self-DNA(8). Here we show how cGAS is sequestered and inhibited by chromatin. We provide a 3.1 A cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which reveals that cGAS does not interact with the nucleosomal DNA, but rather histone 2A/2B, where it is tightly anchored to the "acidic patch". The interaction buries cGAS' DNA binding site B, blocking formation of active cGAS dimers. Acidic patch binding robustly outcompetes agonistic DNA, suggesting that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Altogether, our work shows how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA.

Structural basis for sequestration and autoinhibition of cGAS by chromatin.,Michalski S, de Oliveira Mann CC, Stafford C, Witte G, Bartho J, Lammens K, Hornung V, Hopfner KP Nature. 2020 Sep 10. pii: 10.1038/s41586-020-2748-0. doi:, 10.1038/s41586-020-2748-0. PMID:32911480^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.