小柯机器人

核小体抑制cGAS的结构获解析
2020-09-12 22:06

瑞士洛桑联邦理工学院Andrea Ablasser和瑞士巴塞尔大学Nicolas H. Thomä研究小组合作取得一项新成果。经过不懈努力,他们揭示了核小体抑制cGAS的结构机基础。这一研究成果于2020年9月10日在线发表在《自然》上。

研究人员解析了人cGAS与核小体结合的冷冻电镜结构,其分辨率为3.1Å。cGAS与组蛋白H2A-H2B异二聚体的酸性残基和核小体DNA广泛接触。结构和互补生化分析表明cGAS反过来参与第二个核小体的形成。从机制上讲,与核小体结合将cGAS锁定在单体状态,其空间位阻抑制了基因组DNA的假激活。

研究人员发现cGAS酸性补丁接口突变是消除体外核小体抑制作用所必需的,并且在活细胞中解除cGAS对基因组DNA的抑制。该工作揭示了cGAS与染色质相互作用的结构基础,并揭示了一种可靠的机制,该机制保证cGAS区分自我和非自我的基因组DNA 。

据悉,DNA感受器cGAS在微生物感染、细胞应激和癌症发生时开启先天免疫反应。胞质cGAS被双链DNA激活后产生2'3'环状GMP-AMP,并诱导炎性细胞因子和I型干扰素(IFN)的产生。cGAS也存在于充满基因组DNA的细胞核内,并且染色质与限制其酶活性有关。然而,染色质抑制cGAS的结构基础仍然未知。

附:英文原文

Title: Structural mechanism of cGAS inhibition by the nucleosome

Author: Ganesh R. Pathare, Alexiane Decout, Selene Glck, Simone Cavadini, Kristina Makasheva, Ruud Hovius, Georg Kempf, Joscha Weiss, Zuzanna Kozicka, Baptiste Guey, Pauline Melenec, Beat Fierz, Nicolas H. Thom, Andrea Ablasser

Issue&Volume: 2020-09-10

Abstract: The DNA sensor cGAS initiates innate immune responses following microbial infection, cellular stress, and cancer1. Upon activation by double-stranded DNA, cytosolic cGAS produces 2’3’ cyclic GMP-AMP and triggers inflammatory cytokine and type I interferon (IFN) induction2–7. cGAS is also present inside the cell nucleus replete with genomic DNA8, where chromatin has been implicated in restricting its enzymatic activity9. However, the structural basis for cGAS inhibition by chromatin has remained unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes at 3.1 resolution. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also finds cGAS engaged to a second nucleosome in trans. Mechanistically, nucleosome binding locks cGAS in a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are necessary and sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash cGAS activity on genomic DNA in living cells. Our work uncovers the structural basis of cGAS interaction with chromatin and defines a compelling mechanism that permits self-nonself discrimination of genomic DNA by cGAS.

DOI: 10.1038/s41586-020-2750-6

Source: https://www.nature.com/articles/s41586-020-2750-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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