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细胞核通过感知线粒体DNA断裂增强免疫监视
2021-02-26 15:49

美国斯隆·凯特琳纪念癌症中心Agnel Sfeir课题组发现,细胞核通过感知线粒体DNA断裂增强免疫监控。相关论文于2021年2月25日发表于《自然》杂志。

使用线粒体靶向转录激活因子样效应因子核酸酶(TALENs),研究人员表明线粒体DNA双链断裂(mtDSB)会引起STAT1磷酸化和干扰素刺激基因诱导的I型干扰素反应。线粒体DNA(mtDNA)断裂形成后,由BAX和BAK调控的蛋白将线粒体RNA释放到细胞质中并引起RIG-I-MAVS依赖的免疫反应。通过进一步研究电离辐射治疗后mtDSBs对干扰素信号的影响,研究发现当缺少mtDNA的细胞暴露于伽马射线照射后干扰素刺激基因激活减少。

研究人员还发现,mtDNA断裂与细胞核DNA损伤协同作用来产生强大的细胞免疫应答。因此,研究人员得出结论,线粒体RNA的细胞质积累是细胞应对mtDSB的固有免疫监视机制,包括遗传毒性造成的mtDNA断裂。

据悉,mtDSB具有毒性,其损害mtDNA的完整性并改变线粒体功能。线粒体与细胞核之间的通讯对于维持细胞稳态至关重要。然而,对mtDSBs的核反应仍然未知。

附:英文原文

Title: Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

Author: Marco Tigano, Danielle C. Vargas, Samuel Tremblay-Belzile, Yi Fu, Agnel Sfeir

Issue&Volume: 2021-02-24

Abstract: Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function1. Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown2. Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs)1,3,4, we show that mtDSBs activate a type-I interferon response that involves the phosphorylation of STAT1 and activation of interferon-stimulated genes. After the formation of breaks in the mtDNA, herniation5 mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I–MAVS-dependent immune response. We further investigated the effect of mtDSBs on interferon signalling after treatment with ionizing radiation and found a reduction in the activation of interferon-stimulated genes when cells that lack mtDNA are exposed to gamma irradiation. We also show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Taken together, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including breaks produced by genotoxic agents.

DOI: 10.1038/s41586-021-03269-w

Source: https://www.nature.com/articles/s41586-021-03269-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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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