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ADAR1避免ZBP1诱导的致命的I型干扰素
2022-07-24 12:08
来源：小柯机器人

德国科隆大学Manolis Pasparakis研究组发现，ADAR1避免ZBP1诱导的致命的I型干扰素。相关论文于2022年7月20日在线发表于国际学术期刊《自然》。

研究人员表示，编码RNA脱氨酶的ADAR1基因突变导致与I型干扰素（IFN）反应的慢性激活有关的严重疾病，包括Aicardi-Goutières综合症和双侧纹状体坏死。ADAR1的IFN诱导型p150异构体含有一个Zα结构域，可识别具有替代性左手双螺旋结构的RNA，称为Z-RNA。Zα结构域的杂合ADAR1突变导致人类和小鼠的I型IFN介导的病症；然而，目前仍不清楚ADAR1与Z-RNA的相互作用如何防止IFN的激活。
 
研究人员发现，Z-DNA结合蛋白1（ZBP1）是哺乳动物中已知的唯一一个拥有Zα结构域的蛋白，它能促进I型IFN的激活和ADAR1功能受损的小鼠的致命病变。ZBP1的缺乏或其Zα结构域的突变减少了IFN刺激基因的表达，并在很大程度上防止了具有突变Zα结构域的ADAR1的杂合表达小鼠（Adar1mZα/-小鼠）的出生后早期致死率。Adar1mZα/-小鼠显示出内源性逆转录因子衍生的互补RNA读数的上调和编辑受损，这代表了激活ZBP1的Z-RNA的一个可能的来源。
 
值得注意的是，ZBP1促进了IFN的激活和Adar1mZα/-小鼠的严重病变，其方式与RIPK1、RIPK3、MLKL介导的坏死和caspase-8依赖的凋亡无关，这表明了一种新的作用机制。因此，ADAR1阻止了ZBP1对致病性I型IFN反应的内源性Z-RNA依赖性激活，并表明ZBP1可能对ADAR1突变引起的I型干扰素病有所贡献。
 
附：英文原文
 
Title: ADAR1 averts fatal type I interferon induction by ZBP1

Author: Jiao, Huipeng, Wachsmuth, Laurens, Wolf, Simone, Lohmann, Juliane, Nagata, Masahiro, Kaya, Gksu Gkberk, Oikonomou, Nikos, Kondylis, Vangelis, Rogg, Manuel, Diebold, Martin, Trder, Simon E., Zevnik, Branko, Prinz, Marco, Schell, Christoph, Young, George R., Kassiotis, George, Pasparakis, Manolis

Issue&Volume: 2022-07-20

Abstract: Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi–Goutières syndrome and bilateral striatal necrosis1,2,3. The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA4,5. Hemizygous ADAR1 mutations in the Zα domain cause type I IFN-mediated pathologies in humans2,3 and mice6,7,8; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation. Here we show that Z-DNA-binding protein 1 (ZBP1), the only other protein in mammals known to harbour Zα domains9, promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain (Adar1mZα/– mice). Adar1mZα/– mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1mZα/– mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by ADAR1 mutations.

DOI: 10.1038/s41586-022-04878-9

Source: https://www.nature.com/articles/s41586-022-04878-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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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