染色質螯合和cGAS自抑制的結構基礎
作者：
小柯機器人發布時間：2020/9/12 22:20:18
染色質螯合和cGAS（環狀GMP-AMP合酶）自抑制的結構基礎，這一成果由德國路德維希馬克西米利安慕尼黑大學Karl-Peter Hopfner研究小組經過不懈努力而取得。 相關論文在線發表在2020年9月10日出版的《自然》雜誌上。
在本研究中，研究人員揭示了染色質如何隔離和抑制cGAS。研究人員解析了cGAS催化結構域與核小體結合的3.1Å冷凍電鏡結構，結構表明cGAS不會與核小體DNA相互作用，而是與組蛋白2A / 2B相互作用，它被緊密地錨定在「acidic patch」上。相互作用掩蓋了cGAS的DNA結合位點，阻止了活性cGAS二聚體的形成。
cGAS與acidic patch的結合強度勝過DNA，這表明核小體螯合可以有效抑制cGAS，即使當可接近的DNA在附近時（例如在活躍轉錄的基因組區域）也是如此。總而言之，這項工作揭示了染色質如何隔離細胞核中的cGAS，並提供了防止其與細胞核自身DNA發生自反應的機制。
據悉，cGAS是細胞質微生物DNA的先天免疫感受器。cGAS與DNA結合後誘導信使cGAMP（2′3′環GMP – AMP）的生成，它通過激活STING引起細胞自主防禦以及I型幹擾素和促炎細胞因子的產生。除了對細胞質中微生物DNA有反應外，cGAS還識別錯誤定位於細胞質的自身DNA，並參與自身免疫和無菌炎症反應。對病原體或與損傷相關DNA的特異性識別被認為是由胞質限制引起的。然而，最近的發現表明cGAS穩定的存在於細胞核中，被染色質緊密包裹對於防止其對自身DNA反應至關重要。
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