Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Fang Wang, Kaiying Li, Wensheng Wang, Jiang Hui, Jiangping He, Jin Cai, Wenqing Ren, Yaxing Zhao, Qianqian Song, Yuan He, Yanlei Ma, Xiaona Feng, Yue Liu, Jianqiang Yu, Jitkaew Siriporn, Dan Ma, Zhenyu Cai
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引用次数: 0

Abstract

Excessive DNA damage triggers various types of programmed cell death (PCD), yet the regulatory mechanism of DNA damage-induced cell death is not fully understood. Here, we report that PANoptosis, a coordinated PCD pathway, including pyroptosis, apoptosis and necroptosis, is activated by DNA damage. The Z-DNA binding protein 1 (ZBP1) is the apical sensor of PANoptosis and essential for PANoptosome assembly in response to DNA damage. We find endogenous retroviruses (ERVs) are activated by DNA damage and act as ligands for ZBP1 to trigger PANoptosis. By using ZBP1 knock-out and knock-in mice disrupting ZBP1 nucleic acid-binding activity, we demonstrate that ZBP1-mediated PANoptosis contributes to the toxic effects of chemotherapeutic drugs, which is dependent on ZBP1 nucleic acid-binding activity. We found that ZBP1 expression is downregulated in tumor tissue. Furthermore, in colorectal cancer patients, dsRNA is induced by chemotherapy and sensed by ZBP1 in normal colonic tissues, suggesting ZBP1-mediated PANoptosis is activated by chemotherapy in normal tissues. Our findings indicate that ZBP1-mediated PANoptosis is activated by DNA damage and contributes to the toxic side effects of DNA-damage-based chemotherapy. These data suggest that ZBP1 could be a promising therapeutic target to alleviate chemotherapy-related side effects.

ZBP1 对内源性逆转录病毒衍生 RNA 的感应会触发 DNA 损伤中的泛凋亡,并导致化疗的毒副作用。
过度的DNA损伤会引发各种类型的程序性细胞死亡(PCD),但DNA损伤诱导细胞死亡的调控机制尚未完全明了。在这里,我们报告了DNA损伤激活的PANoptosis--一种协调的PCD途径,包括热凋亡、细胞凋亡和坏死。Z-DNA 结合蛋白 1(ZBP1)是 PANoptosis 的顶端传感器,在 DNA 损伤时对 PANoptosome 的组装至关重要。我们发现内源性逆转录病毒(ERV)会被DNA损伤激活,并作为ZBP1的配体触发PAN凋亡。通过利用 ZBP1 基因敲除和基因敲入小鼠破坏 ZBP1 的核酸结合活性,我们证明了 ZBP1 介导的 PAN 细胞凋亡有助于化疗药物的毒性作用,而这依赖于 ZBP1 的核酸结合活性。我们发现 ZBP1 在肿瘤组织中表达下调。此外,在结直肠癌患者中,化疗会诱导dsRNA,而正常结肠组织中的ZBP1会感应到dsRNA,这表明ZBP1介导的PAN凋亡在正常组织中被化疗激活。我们的研究结果表明,ZBP1 介导的 PAN 细胞凋亡被 DNA 损伤激活,并导致了基于 DNA 损伤的化疗的毒副作用。这些数据表明,ZBP1 可能是缓解化疗相关副作用的一个有前途的治疗靶点。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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