内部收益率3
先天免疫系统
TFAM公司
干扰素基因刺激剂
生物
细胞生物学
坦克结合激酶1
干扰素
线粒体DNA
线粒体
磷酸化
免疫系统
免疫学
蛋白激酶A
生物化学
线粒体生物发生
基因
丝裂原活化蛋白激酶激酶
作者
Quanwei Li,Shaofeng Wang,Pan Guo,Yuanhong Feng,Wenlan Yu,Hui Zhang,Jianying Guo,Ying Li,Lianmei Hu,Jiang Pan,Jianzhao Liao,Zhaoxin Tang
标识
DOI:10.1016/j.scitotenv.2023.167315
摘要
Copper (Cu) is pollution metal that is a global concern due to its toxic effects. A recent study found that the release of mitochondrial DNA (mtDNA) into the cytoplasm can activate the innate immune response, but the exact mechanisms underlying the effect of Cu exposure remains unknown. In this study, we identified that the reduction in transcription Factor A (TFAM) led to mtDNA leakage into the cytoplasm under Cu exposure in hepatocytes, accompanied by the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway-mediated innate immunity (increased expression of cGAS, STING, TANK-binding kinase-1 (TBK1), and interferon regulatory factor-3 (IRF3)) genes and proteins, and enhanced phosphorylation levels of TBK1 and IRF3). Subsequently, silencing TFAM (siTFAM) significantly aggravated mtDNA release and the innate immune response under Cu treatment. Mitochondrial DNA depletion alleviated Cu-induced innate immunity in hepatocytes, while mtDNA transfection further enhanced the innate immune response. Notably, the inhibition of STING effectively alleviated the phosphorylation levels of the TBK1 and IRF3 proteins induced by Cu, while the upregulation of STING aggravated the Cu-induced innate immunity. Furthermore, EtBr and H-151(a STING inhibitor) treatment dramatically reversed the effect of TFAM depletion on the sharpened innate immune response induced by Cu via the cGAS-STING pathway. In general, these findings demonstrated the TFAM deficiency promotes innate immunity by activating the mtDNA-cGAS-STING signalling pathway under Cu exposure in hepatocytes, providing new insight into Cu toxicology.
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