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Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS
The Journal of Immunology ( IF 4.4 ) Pub Date : 2021-10-15 , DOI: 10.4049/jimmunol.2100392
Kun Song 1 , Yakun Wu 1 , Bishi Fu 2 , Lingyan Wang 1 , Wenzhuo Hao 1 , Fang Hua 1 , Yiwen Sun 1 , Martin E Dorf 3 , Shitao Li 4
Affiliation  

Cytosolic DNA from pathogens activates the DNA sensor cyclic GMP–AMP (cGAMP) synthase (cGAS) that produces the second messenger, cGAMP. cGAMP triggers a signal cascade leading to type I IFN expression. Host DNA is normally restricted in the cellular compartments of the nucleus and mitochondria. Recent studies have shown that DNA virus infection triggers mitochondrial stress, leading to the release of mitochondrial DNA to the cytosol and activation of cGAS; however, the regulatory mechanism of mitochondrial DNA-mediated cGAS activation is not well elucidated. In this study, we analyzed cGAS protein interactome in mouse RAW264.7 macrophages and found that cGAS interacted with C1QBP. C1QBP predominantly localized in the mitochondria and leaked into the cytosol during DNA virus infection. The leaked C1QBP bound the NTase domain of cGAS and inhibited cGAS enzymatic activity in cells and in vitro. Overexpression of the cytosolic form of C1QBP inhibited cytosolic DNA-elicited innate immune responses and promoted HSV-1 infection. By contrast, deficiency of C1QBP led to the elevated innate immune responses and impaired HSV-1 infection. Taken together, our study suggests that C1QBP is a novel cGAS inhibitor hidden in the mitochondria.



中文翻译:

泄漏的线粒体 C1QBP 抑制 DNA 传感器 cGAS 的激活

来自病原体的细胞溶质 DNA 会激活产生第二信使 cGAMP 的 DNA 传感器环 GMP-AMP (cGAMP) 合酶 (cGAS)。cGAMP 触发信号级联,导致 I 型 IFN 表达。宿主 DNA 通常限制在细胞核和线粒体的细胞区室中。最近的研究表明,DNA病毒感染会引发线粒体应激,导致线粒体DNA释放到细胞质中并激活cGAS;然而,线粒体DNA介导的cGAS激活的调节机制尚不清楚。在本研究中,我们分析了小鼠 RAW264.7 巨噬细胞中的 cGAS 蛋白相互作用组,发现 cGAS 与 C1QBP 相互作用。C1QBP 主要定位于线粒体并在 DNA 病毒感染期间泄漏到细胞质中。泄漏的 C1QBP 与 cGAS 的 NTase 结构域结合,并在细胞和体外抑制 cGAS 酶活性。C1QBP 胞质形式的过表达抑制胞质 DNA 引发的先天免疫反应并促进 HSV-1 感染。相比之下,C1QBP 的缺乏导致先天免疫反应升高和 HSV-1 感染受损。总之,我们的研究表明 C1QBP 是一种隐藏在线粒体中的新型 cGAS 抑制剂。

更新日期:2021-10-06
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