小柯机器人

ZBP1介导的端粒至线粒体信号介导复制危机
2023-02-12 15:25

美国索尔克生物研究所Jan Karlseder和Gerald S. Shadel共同合作,近期取得重要工作进展。他们研究发现,ZBP1介导的端粒至线粒体信号介导复制危机。相关研究成果2023年2月8日在线发表于《自然》杂志上。

据介绍,癌症是通过遗传和表观遗传改变的积累而产生的,这些改变使细胞能够避开基于端粒的增殖障碍并实现永生。其中一个障碍是复制危机,这是一个依赖自噬的程序,可以消除端粒不稳定的检查点缺陷细胞和其他与癌症相关的染色体畸变。然而,对于调节这一重要肿瘤抑制屏障发病的分子事件知之甚少。

研究人员鉴定了先天免疫传感器Z-DNA结合蛋白1(ZBP1)作为危机程序的调节因子。ZBP1的危机相关亚型由cGAS–STING DNA传感途径诱导,但只有当与功能失调的端粒合成的含有端粒重复序列的RNA(TERRA)转录物相关时才能达到完全激活。TERRA结合的ZBP1在线粒体外膜上寡聚成细丝,在那里激活先天免疫适配器蛋白线粒体抗病毒信号蛋白(MAVS)。研究人员认为ZBP1的这些寡聚特性是一种信号放大机制,其中TERRA–ZBP1相互作用很少,足以启动有害的MAVS依赖性干扰素反应。

总之,这一研究揭示了端粒介导的肿瘤抑制机制,即功能失调的端粒通过线粒体TERRA–ZBP1复合物激活先天免疫反应,以消除注定要进行肿瘤转化的细胞。

附:英文原文

Title: Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

Author: Nassour, Joe, Aguiar, Lucia Gutierrez, Correia, Adriana, Schmidt, Tobias T., Mainz, Laura, Przetocka, Sara, Haggblom, Candy, Tadepalle, Nimesha, Williams, April, Shokhirev, Maxim N., Akincilar, Semih C., Tergaonkar, Vinay, Shadel, Gerald S., Karlseder, Jan

Issue&Volume: 2023-02-08

Abstract: Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis—an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS–STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA–ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA–ZBP1 complexes to eliminate cells destined for neoplastic transformation.

DOI: 10.1038/s41586-023-05710-8

Source: https://www.nature.com/articles/s41586-023-05710-8

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
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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