The paper published online in the journal Cell Research. [Photo/WeChat account of Biophysical Society of China]

Researchers from the Institute of Biophysics, Chinese Academy of Sciences, published a research paper entitled the "Structural basis for nucleosome-mediated inhibition of cGAS activity" online in the journal Cell Research.

The paper reports two cryo-electron microscopic structures of cyclic GMP-AMP synthase (cGAS)-nucleosome complexes and provides structural insights into the inhibition of cGAS activity by the nucleosome -- as well as advances the understanding of the mechanism by which hosts avoid the autoimmune attack caused by cGAS.

Activation of cGAS through sensing cytosolic double stranded DNA (dsDNA) plays a pivotal role in innate immunity against exogenous infections, as well as cellular regulation under stress. Aberrant activation of cGAS induced by self-DNA is related to autoimmune diseases.

cGAS accumulates at chromosomes during mitosis or spontaneously in the nucleus. Binding of cGAS to the nucleosome competitively attenuates the dsDNA-mediated cGAS activation, but the molecular mechanism of the attenuation is still poorly understood.

The structures of cGAS–nucleosome complexes reported in the paper reveal that cGAS interacts with the nucleosome as a monomer, forming 1:1 and 2:2 complexes, respectively. cGAS contacts the nucleosomal acidic patch formed by the H2A–H2B heterodimer through the dsDNA-binding site B in both complexes and could interact with the DNA from the other symmetrically placed nucleosome via the dsDNA-binding site C in the 2:2 complex. 

The bound nucleosome inhibits the activation of cGAS by blocking the interaction of cGAS with ligand dsDNA and disrupting cGAS dimerization. R236A or R255A mutation of cGAS impairs the binding between cGAS and the nucleosome and largely relieves the nucleosome-mediated inhibition of cGAS activity.