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2023, Nature. DOI: 10.1038/s41586-023-05710-8
Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
Joe Nassour, Lucia Gutierrez Aguiar, Adriana Correia, Tobias T. Schmidt, Laura Mainz, Sara Przetocka, Candy Haggblom, Nimesha Tadepalle, April Williams, Maxim N. Shokhirev, Semih C. Akincilar, Vinay Tergaonkar, Gerald S. Shadel, Jan Karlseder
Abstract:
AbstractCancers 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.
2023-11-30 21:45:00
#paper https://doi.org/10.1038/s41586-023-05710-8 Nassour, J., Aguiar, L.G., Correia, A. et al. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis. Nature 614, 767–773 (2023). 这篇文献主要是发现了永生化细胞不死的机制,通过讲端粒、衰老和和免疫结合起来,从侧面为肿瘤细胞的异常增殖提供了新的思路。全文仅仅用了简单的WB和免疫荧光等技术,完成了比较有创新性的课题并发表在了nature上。整篇文献发现永生化细胞中ZBP1表达升高和I型干扰素信号通路激活,通过分析发现ZBP1可以与端粒不稳定相关RNA结合并定位于线粒体上,从而激活MAVS和下游I型干扰素信号通路维持细胞的生长,而端粒的不稳定又会激活cGAS信号通路,引起I型干扰素信号通路激活导致ZBP1升高,从而形成了一个环路。
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