Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Cell Death Differ. 2024 Jul;31(7):924-937. doi: 10.1038/s41418-024-01320-7. Epub 2024 Jun 7.
Mitochondria react to infection with sub-lethal signals in the apoptosis pathway. Mitochondrial signals can be inflammatory but mechanisms are only partially understood. We show that activation of the caspase-activated DNase (CAD) mediates mitochondrial pro-inflammatory functions and substantially contributes to host defense against viral infection. In cells lacking CAD, the pro-inflammatory activity of sub-lethal signals was reduced. Experimental activation of CAD caused transient DNA-damage and a pronounced DNA damage response, involving major kinase signaling pathways, NF-κB and cGAS/STING, driving the production of interferon, cytokines/chemokines and attracting neutrophils. The transcriptional response to CAD-activation was reminiscent of the reaction to microbial infection. CAD-deficient cells had a diminished response to viral infection. Influenza virus infected CAD-deficient mice displayed reduced inflammation in lung tissue, higher viral titers and increased weight loss. Thus, CAD links the mitochondrial apoptosis system and cell death caspases to host defense. CAD-driven DNA damage is a physiological element of the inflammatory response to infection.
线粒体对细胞凋亡途径中的亚致死信号做出反应。线粒体信号可以是炎症性的，但机制尚不完全清楚。我们表明，半胱氨酸天冬氨酸蛋白酶（caspase）激活的脱氧核糖核酸酶（CAD）的激活介导了线粒体的促炎功能，并为宿主抵抗病毒感染提供了重要防御。在缺乏 CAD 的细胞中，亚致死信号的促炎活性降低。CAD 的实验激活导致短暂的 DNA 损伤和明显的 DNA 损伤反应，涉及主要的激酶信号通路、NF-κB 和 cGAS/STING，从而驱动干扰素、细胞因子/趋化因子的产生并吸引中性粒细胞。对 CAD 激活的转录反应类似于对微生物感染的反应。CAD 缺陷细胞对病毒感染的反应减弱。流感病毒感染 CAD 缺陷小鼠后，肺部组织的炎症减轻，病毒滴度升高，体重减轻增加。因此，CAD 将线粒体凋亡系统和细胞死亡半胱天冬酶与宿主防御联系起来。CAD 驱动的 DNA 损伤是感染炎症反应的生理组成部分。
