A core viral protein binds host nucleosomes to sequester immune danger signals.
A core viral protein binds host nucleosomes to sequester immune danger signals.
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DOI：
10.1038/nature18317
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发表时间：
2016-07-07
期刊：
影响因子：
64.8
通讯作者：
Weitzman MD
中科院分区：
文献类型：
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作者：
Avgousti DC;Herrmann C;Kulej K;Pancholi NJ;Sekulic N;Petrescu J;Molden RC;Blumenthal D;Paris AJ;Reyes ED;Ostapchuk P;Hearing P;Seeholzer SH;Worthen GS;Black BE;Garcia BA;Weitzman MD
病毒蛋白模仿宿主蛋白的结构和功能，重定向细胞过程并破坏先天防御。小的基本蛋白质紧密结合并调节病毒和细胞DNA基因组。核小体是细胞染色质的重复单位，在先天免疫应答中起重要作用。病毒编码的核心基本蛋白紧凑病毒基因组，但其对宿主染色质结构和功能的影响仍未被探索。腺病毒编码一种高度碱性的蛋白，叫做蛋白VII，类似于细胞组蛋白。虽然蛋白VII与病毒DNA结合，并与病毒基因组结合到病毒颗粒中，但蛋白VII是否影响细胞染色质尚不清楚。我们观察到蛋白VII改变了细胞染色质，这使我们假设这影响了腺病毒感染期间的抗病毒反应。我们发现蛋白VII与核小体形成复合物并限制DNA的可及性。我们确定了负责染色质定位的蛋白VII的翻译后修饰。此外，蛋白质组学分析表明，蛋白VII足以改变宿主染色质的蛋白质组成。我们发现蛋白VII对于高迁移率组蛋白B家族成员（HMGB1、HMGB2和HMGB3）的染色质保留是必要和充分的。HMGB1在炎症刺激下积极释放，并作为激活免疫反应的危险信号。我们发现蛋白VII可以在体外直接结合HMGB1，并进一步证明蛋白VII在小鼠肺中的表达足以降低炎症诱导的HMGB1含量和支气管肺泡灌洗液中中性粒细胞的募集。我们的体外和体内实验结果表明，蛋白VII可以隔离HMGB1并阻止其释放。本研究揭示了一种利用核小体结合来控制细胞外免疫信号的病毒策略。
Viral proteins mimic host protein structure and function to redirect cellular processes and subvert innate defenses. Small basic proteins compact and regulate both viral and cellular DNA genomes. Nucleosomes are the repeating units of cellular chromatin and play an important role in innate immune responses. Viral encoded core basic proteins compact viral genomes but their impact on host chromatin structure and function remains unexplored. Adenoviruses encode a highly basic protein called protein VII that resembles cellular histones. Although protein VII binds viral DNA and is incorporated with viral genomes into virus particles, it is unknown whether protein VII impacts cellular chromatin. Our observation that protein VII alters cellular chromatin led us to hypothesize that this impacts antiviral responses during adenovirus infection. We found that protein VII forms complexes with nucleosomes and limits DNA accessibility. We identified post-translational modifications on protein VII that are responsible for chromatin localization. Furthermore, proteomic analysis demonstrated that protein VII is sufficient to alter protein composition of host chromatin. We found that protein VII is necessary and sufficient for retention in chromatin of members of the high-mobility group protein B family (HMGB1, HMGB2, and HMGB3). HMGB1 is actively released in response to inflammatory stimuli and functions as a danger signal to activate immune responses. We showed that protein VII can directly bind HMGB1 in vitro and further demonstrated that protein VII expression in mouse lungs is sufficient to decrease inflammation-induced HMGB1 content and neutrophil recruitment in the bronchoalveolar lavage fluid. Together our in vitro and in vivo results show that protein VII sequesters HMGB1 and can prevent its release. This study uncovers a viral strategy in which nucleosome binding is exploited to control extracellular immune signaling.