日本东京大学Hitoshi Kurumizaka和美国洛克菲勒大学Hironori Funabiki课题组合作，解析了核小体抑制环状GMP-AMP合酶（cGAS）的结构基础。2020年9月10日，国际学术期刊《科学》发表了这一成果。

研究人员揭示了核小体抑制cGAS的结构基础。人cGAS-核小体核心颗粒（NCP）复合物的冷冻电镜结构表明，两个cGAS单体通过结合H2A-H2B的酸性patch而与核小体DNA的两个NCP桥接。在这种结构中，cGAS激活所需的所有三个已知DNA结合位点都被重新利用或变得不可及，这抑制了cGAS的二聚化（激活的另一个先决条件）。cGAS连接和酸性patch关键残基的突变可减弱核小体的抑制作用。这项研究揭示了染色体自身DNA如何沉默cGAS。

据介绍，cGAS感知入侵的病原DNA并产生炎症信号、自噬和凋亡。之前研究表明宿主DNA组装成核小体以限制cGAS自激活，但其潜在机制尚不清楚。

附：英文原文

Title: Structural basis for the inhibition of cGAS by nucleosomes

Author: Tomoya Kujirai, Christian Zierhut, Yoshimasa Takizawa, Ryan Kim, Lumi Negishi, Nobuki Uruma, Seiya Hirai, Hironori Funabiki, Hitoshi Kurumizaka

Issue&Volume: 2020/09/10

Abstract: The cyclic GMP-AMP 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-EM structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of H2A-H2B 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.

DOI: 10.1126/science.abd0237

Source: https://science.sciencemag.org/content/early/2020/09/09/science.abd0237