小柯机器人

Z核酸感应触发Z-DNA结合蛋白1（ZBP1）依赖性坏死和炎症，这一成果由德国科隆大学Manolis Pasparakis团队经过不懈努力而取得。2020年3月25日，国际学术期刊《自然》在线发表了这一成果。

研究人员发现在表达RIPK1 RIP同型相互作用基序（RHIM）突变（Ripk1^{mR / mR}）的小鼠中，Zα依赖的内源性配体感知诱导ZBP1介导的围产期致死；在表皮特异性RIPK1缺失（RIPK1^E-KO）的小鼠中引发皮肤炎和肠上皮特异性FADD缺失（FADD^IEC-KO）的小鼠诱发结肠炎。同样地，在用caspase抑制剂处理或表达RIPK1 RHIM突变的成纤维细胞中ZBP1诱导的坏死需要功能性Zα结构域。在细胞核中抑制核输出诱发Zα依赖的RIPK3活化，导致细胞死亡，这表明ZBP1可能识别核Z型核酸。研究发现ZBP1以Zα依赖的方式组成性结合细胞双链RNA。在表皮RNA中检测到了内源性逆转录元件的互补片段，这表明源自这些逆转录元件的双链RNA可能充当触发ZBP1激活的Zα结构域配体。总体而言，该研究结果提供了证据，表明ZBP1感知内源性Z型核酸会引发RIPK3依赖的坏死和炎症，这可能是慢性炎症发展的基础，尤其是在RIPK1和CASP8突变的个体中。

据介绍，人们对Z-DNA和Z-RNA（即具有左手双螺旋结构的核酸）的生物学功能知之甚少。Z-DNA结合蛋白1（ZBP1；也称为DAI或DLM-1）是一种核酸传感器，它包含两个与Z-DNA和Z-RNA结合的Zα结构域。ZBP1通过感知病毒核酸介导宿主防御某些病毒。在小鼠中RIPK1缺失或RHIM的突变会引发ZBP1依赖性坏死和炎症。但是，在没有病毒感染的情况下诱导ZBP1激活的机制仍然未知。

附：英文原文

Title: Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation

Author: Huipeng Jiao, Laurens Wachsmuth, Snehlata Kumari, Robin Schwarzer, Juan Lin, Remzi Onur Eren, Amanda Fisher, Rebecca Lane, George R. Young, George Kassiotis, William J. Kaiser, Manolis Pasparakis

Issue&Volume: 2020-03-25

Abstract: The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood1,2,3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Zα domains that bind Z-DNA4,5 and Z-RNA6,7,8. ZBP1 mediates host defence against some viruses6,7,9,10,11,12,13,14 by sensing viral nucleic acids6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADDIEC-KO). Consistently, functional Zα domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Zα-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Zα-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Zα-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions—particularly in individuals with mutations in RIPK1 and CASP817,18,19,20.

DOI: 10.1038/s41586-020-2129-8

Source: https://www.nature.com/articles/s41586-020-2129-8

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
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