Structural basis for the inhibition of cGAS by nucleosomes


Saving a host cell from itself

A fundamental mammalian defense mechanism against pathogens and damaged cellular DNA is to recognize DNA fragments in the cytosol and trigger an inflammatory response. The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) that recognizes cytosolic DNA is also found in the nucleus, but here its activity is suppressed by tethering to chromatin. Two papers now report cryo–electron microscopy structures of cGAS bound to the nucleosome core particle (NCP). Kujirai et al. observed a structure with two cGAS molecules bridging two NCPs, whereas Boyer et al. observed cGAS bound to a single nucleosome. Together, these structures show how cGAS is prevented from autoreactivity toward host DNA.

Science, this issue p. 455, p. 450

Abstract

The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo–electron microscopy structure of the human cGAS–nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.



Source link