Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis.
Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis.
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DOI：
10.1016/j.celrep.2023.113377
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发表时间：
2023-11
期刊：
影响因子：
8.8
通讯作者：
Tao Yang;Guodong Wang;Mingxiang Zhang;Xiaohu Hu;Qi Li;Fenglin Yun;Yingying Xing;Xinyang Song;Haibing Zhang;Guohong Hu;Youcun Qian
中科院分区：
文献类型：
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作者：
Tao Yang;Guodong Wang;Mingxiang Zhang;Xiaohu Hu;Qi Li;Fenglin Yun;Yingying Xing;Xinyang Song;Haibing Zhang;Guohong Hu;Youcun Qian
ZBP1 感知病毒 Z-RNA，诱导坏死性细胞死亡，从而抑制病毒感染。 ZBP1 还被认为可以识别宿主细胞衍生的 Z-RNA，从而调节小鼠的器官发育和组织炎症。然而，宿主来源的 Z-RNA 是如何形成的以及 ZBP1 如何感知这些内源 Z-RNA 仍不清楚。在这里，我们报告氧化应激强烈诱导宿主细胞内源性 Z-RNA，然后 Z-RNA 定位到应激颗粒，由 ZBP1 直接感知，从而触发坏死性凋亡。氧化应激触发肿瘤细胞中 Z-RNA 水平急剧增加，然后 Z-RNA 通过 ZBP1 直接触发肿瘤细胞坏死性凋亡。诱导的 Z-RNA 定位到应激颗粒对于 ZBP1 传感至关重要。氧化应激诱导的 Z-RNA 通过 ZBP1 驱动的坏死性凋亡显着促进肿瘤化疗。因此，我们的研究确定氧化应激是 Z-RNA 形成的关键触发因素，并演示了 ZBP1 如何直接感知 Z-RNA 以触发抗肿瘤坏死性细胞死亡。
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.