Structural basis for the inhibition of cGAS by nucleosomes

doi:10.1126/science.abd0237

GSTDTAP > 气候变化

DOI	10.1126/science.abd0237
	Structural basis for the inhibition of cGAS by nucleosomes
	Tomoya Kujirai; Christian Zierhut; Yoshimasa Takizawa; Ryan Kim; Lumi Negishi; Nobuki Uruma; Seiya Hirai; Hironori Funabiki; Hitoshi Kurumizaka
	2020-10-23
发表期刊	Science
出版年	2020
英文摘要	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][1], p. [450][2] 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. [1]: /lookup/doi/10.1126/science.abd0237 [2]: /lookup/doi/10.1126/science.abd0609
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/300296
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Tomoya Kujirai,Christian Zierhut,Yoshimasa Takizawa,et al. Structural basis for the inhibition of cGAS by nucleosomes[J]. Science,2020.
APA	Tomoya Kujirai.,Christian Zierhut.,Yoshimasa Takizawa.,Ryan Kim.,Lumi Negishi.,...&Hitoshi Kurumizaka.(2020).Structural basis for the inhibition of cGAS by nucleosomes.Science.
MLA	Tomoya Kujirai,et al."Structural basis for the inhibition of cGAS by nucleosomes".Science (2020).