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染色质螯合和cGAS自抑制的结构基础
2020-09-12 22:20

染色质螯合和cGAS(环状GMP-AMP合酶)自抑制的结构基础,这一成果由德国路德维希马克西米利安慕尼黑大学Karl-Peter Hopfner研究小组经过不懈努力而取得。 相关论文在线发表在2020年9月10日出版的《自然》杂志上。

在本研究中,研究人员揭示了染色质如何隔离和抑制cGAS。研究人员解析了cGAS催化结构域与核小体结合的3.1Å冷冻电镜结构,结构表明cGAS不会与核小体DNA相互作用,而是与组蛋白2A / 2B相互作用,它被紧密地锚定在“acidic patch”上。相互作用掩盖了cGAS的DNA结合位点,阻止了活性cGAS二聚体的形成。

cGAS与acidic patch的结合强度胜过DNA,这表明核小体螯合可以有效抑制cGAS,即使当可接近的DNA在附近时(例如在活跃转录的基因组区域)也是如此。总而言之,这项工作揭示了染色质如何隔离细胞核中的cGAS,并提供了防止其与细胞核自身DNA发生自反应的机制。

据悉,cGAS是细胞质微生物DNA的先天免疫感受器。cGAS与DNA结合后诱导信使cGAMP(2′3′环GMP – AMP)的生成,它通过激活STING引起细胞自主防御以及I型干扰素和促炎细胞因子的产生。除了对细胞质中微生物DNA有反应外,cGAS还识别错误定位于细胞质的自身DNA,并参与自身免疫和无菌炎症反应。对病原体或与损伤相关DNA的特异性识别被认为是由胞质限制引起的。然而,最近的发现表明cGAS稳定的存在于细胞核中,被染色质紧密包裹对于防止其对自身DNA反应至关重要。

附:英文原文

Title: Structural basis for sequestration and autoinhibition of cGAS by chromatin

Author: Sebastian Michalski, Carina C. de Oliveira Mann, Che Stafford, Gregor Witte, Joseph Bartho, Katja Lammens, Veit Hornung, Karl-Peter Hopfner

Issue&Volume: 2020-09-10

Abstract: cGAS (cyclic GMP–AMP synthase) is an innate immune sensor for cytosolic microbial DNA1. Upon binding DNA, it synthesizes the messenger cGAMP (2’3’ cyclic GMP–AMP)2–4, which triggers cell-autonomous defense and the production of type I interferons and pro-inflammatory cytokines via activation of STING5. Besides responding to cytosolic microbial DNA, cGAS also recognizes mis-localized cytosolic self-DNA and is implicated in autoimmunity and sterile inflammation6,7. Specificity towards pathogen or damage associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus8–10, where tight chromatin tethering is even important to prevent autoreactivity to self-DNA8. Here we show how cGAS is sequestered and inhibited by chromatin. We provide a 3.1 cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which reveals that cGAS does not interact with the nucleosomal DNA, but rather histone 2A/2B, where it is tightly anchored to the “acidic patch”. The interaction buries cGAS’ DNA binding site B, blocking formation of active cGAS dimers. Acidic patch binding robustly outcompetes agonistic DNA, suggesting that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Altogether, our work shows how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA.

DOI: 10.1038/s41586-020-2748-0

Source: https://www.nature.com/articles/s41586-020-2748-0

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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