Structural mechanism of cGAS inhibition by nuclei

DNA sensor cGAS initiates innate immune response after microbial infection, cellular stress and cancer1. Upon activation by double-stranded DNA, cytosolic CGAS produces 2’3 ‘cyclic GMP-AMPs and drives inflammatory cytokine and type I interferon (IFN) induction2-7. CGAS is also present inside the cell nucleus with genomic DNA8, Where chromatin has been implicated in restricting its enzymic activity9. However, the structural basis of cGAS inhibition by chromatin remains unknown. Here we 3.1. Present the cryo-electron microscopy structure of human cGAS bound to nucleosomes at resolution. cGAS histones make extensive contact with both acidic patches of H2A – H2B heterodimer and nucleosomal DNA. Structural and complementary biochemical analyzes also detect CGAS associated with each other’s nucleus. In trance. Mechanistically, nucleosome binding CGAS occurs in a monomeric state, in which the steric hindrance suppresses its activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are necessary and sufficient to eliminate the inhibitory effect of the nucleus. in vitro And exposing CGAS activity on genomic DNA in living cells. Our work exposes the structural basis of cGAS interaction with chromatin and defines a compelling mechanism that allows self-inconsistent differentiation of genomic DNA by cGAS.