通过 ZBP1 依赖性坏死性凋亡触发内源性 Z-RNA 感应的抗肿瘤治疗。
Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis.
机构信息
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
出版信息
Cell Rep. 2023 Nov 28;42(11):113377. doi: 10.1016/j.celrep.2023.113377. Epub 2023 Nov 3.
ZBP1 senses viral Z-RNAs to induce necroptotic cell death to restrain viral infection. ZBP1 is also thought to recognize host cell-derived Z-RNAs to regulate organ development and tissue inflammation in mice. However, it remains unknown how the host-derived Z-RNAs are formed and how these endogenous Z-RNAs are sensed by ZBP1. Here, we report that oxidative stress strongly induces host cell endogenous Z-RNAs, and the Z-RNAs then localize to stress granules for direct sensing by ZBP1 to trigger necroptosis. Oxidative stress triggers dramatically increase Z-RNA levels in tumor cells, and the Z-RNAs then directly trigger tumor cell necroptosis through ZBP1. Localization of the induced Z-RNAs to stress granules is essential for ZBP1 sensing. Oxidative stress-induced Z-RNAs significantly promote tumor chemotherapy via ZBP1-driven necroptosis. Thus, our study identifies oxidative stress as a critical trigger for Z-RNA formation and demonstrates how Z-RNAs are directly sensed by ZBP1 to trigger anti-tumor necroptotic cell death.
ZBP1 可识别病毒 Z-RNAs，引发细胞发生坏死性细胞死亡，从而抑制病毒感染。人们认为 ZBP1 还可以识别宿主细胞来源的 Z-RNAs，从而调节小鼠的器官发育和组织炎症。然而，目前尚不清楚这些宿主来源的 Z-RNAs 是如何形成的，以及这些内源性 Z-RNAs 是如何被 ZBP1 识别的。在这里，我们报告氧化应激强烈诱导宿主细胞内源性 Z-RNAs 的形成，然后这些 Z-RNAs 定位于应激颗粒，直接被 ZBP1 识别，从而引发细胞发生坏死性细胞死亡。氧化应激会导致肿瘤细胞中 Z-RNA 水平显著升高，然后这些 Z-RNAs 通过 ZBP1 直接触发肿瘤细胞坏死性细胞死亡。诱导产生的 Z-RNAs 定位于应激颗粒对于 ZBP1 的识别至关重要。氧化应激诱导的 Z-RNAs 通过 ZBP1 驱动的坏死性细胞死亡显著促进肿瘤的化学疗法。因此，本研究确定氧化应激是 Z-RNA 形成的关键触发因素，并阐明了 Z-RNAs 如何被 ZBP1 直接识别，从而引发抗肿瘤坏死性细胞死亡。
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