小柯机器人

美国德州农工大学A. Phillip West团队发现，ZBP1和cGAS对线粒体DNA的合作感应促进心脏毒性的产生。2023年6月22日，《细胞》杂志在线发表了这项成果。

研究人员表明，线粒体基因组的不稳定性促进了Z型DNA的积累。Z-DNA结合蛋白1（ZBP1）稳定Z型线粒体DNA（mtDNA），并形成一个包含cGAS、RIPK1和RIPK3的细胞膜复合物，以维持STAT1的磷酸化和I型干扰素（IFN-I）信号传导。在暴露于多柔比星后，心肌细胞中观察到Z型mtDNA升高、ZBP1表达和IFN-I信号。多柔比星是一种一线化疗药物，在癌症患者中经常引起心脏毒性。令人震惊的是，缺乏ZBP1或IFN-I信号的小鼠可以免受多柔比星诱导的心脏毒性。这些研究结果显示，ZBP1是cGAS的合作伙伴，维持IFN-I对线粒体基因组不稳定的反应，并强调ZBP1是心力衰竭和其他mtDNA压力导致干扰素相关病理学的潜在靶点。

据了解，mtDNA是先天性免疫系统的强效激动剂；然而，mtDNA的确切免疫刺激特征和细胞核酸传感器的检测动力学仍然定义不清。

附：英文原文

Title: Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Author: Yuanjiu Lei, Jordyn J. VanPortfliet, Yi-Fan Chen, Joshua D. Bryant, Ying Li, Danielle Fails, Sylvia Torres-Odio, Katherine B. Ragan, Jingti Deng, Armaan Mohan, Bing Wang, Olivia N. Brahms, Shawn D. Yates, Michael Spencer, Carl W. Tong, Marcus W. Bosenberg, Laura Ciaccia West, Gerald S. Shadel, Timothy E. Shutt, Jason W. Upton, Pingwei Li, A. Phillip West

Issue&Volume: 2023-06-22

Abstract: Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.

DOI: 10.1016/j.cell.2023.05.039

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00591-3