小柯机器人

美国华盛顿大学Andrew Oberst研究组取得一项新突破。他们的研究发现ADAR1突变引起Z-DNA结合域1(ZBD1)依赖性免疫。该项研究成果发表在2022年7月20日出版的《自然》上。

研究人员发现由ADAR1蛋白ZBD改变引起的疾病是由ZBP1激活驱动的。研究发现ZBP1缺失完全挽救了由ADAR1改变引起的疾病，而没有完全逆转由这种改变引起的潜在炎症。虽然RIPK3的缺失部分重现了ZBP1缺失的保护作用，但caspase 8和RIPK3或caspase 8和MLKL的双缺失却意外地加剧了由ADAR1改变引发的致病。这些发现表明ADAR1是ZBP1激活的负调节因子，并且ZBP1依赖性信号传导是ADAR1改变引起自身炎症病理学的基础。

据介绍，RNA编辑酶ADAR1对于抑制由自身RNA异常识别引起的先天免疫激活和病理是必不可少的，它通过破坏内源双链RNA物种的双链结构来发挥功能。ADAR1蛋白ZBD编码序列中的点突变与严重自身炎症性疾病相关。ZBP1是唯一含有ZBD的哺乳动物蛋白，它的激活可以通过激酶RIPK1和RIPK3以及蛋白酶caspase 8引发细胞死亡和转录反应。

附：英文原文

Title: ADAR1 mutation causes ZBP1-dependent immunopathology

Author: Hubbard, Nicholas W., Ames, Joshua M., Maurano, Megan, Chu, Lan H., Somfleth, Kim Y., Gokhale, Nandan S., Werner, Margo, Snyder, Jessica M., Lichauco, Katrina, Savan, Ram, Stetson, Daniel B., Oberst, Andrew

Issue&Volume: 2022-07-20

Abstract: The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3,4,5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase8 (refs.7,8,9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase8 and RIPK3, or of caspase8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.

DOI: 10.1038/s41586-022-04896-7

Source: https://www.nature.com/articles/s41586-022-04896-7

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/
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