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mtDNA Activates cGAS Signaling and Suppresses the YAP-Mediated Endothelial Cell Proliferation Program to Promote Inflammatory Injury.
Immunity ( IF 25.5 ) Pub Date : 2020-03-11 , DOI: 10.1016/j.immuni.2020.02.002 Long Shuang Huang 1 , Zhigang Hong 1 , Wei Wu 2 , Shiqin Xiong 1 , Ming Zhong 2 , Xiaopei Gao 1 , Jalees Rehman 3 , Asrar B Malik 1
Immunity ( IF 25.5 ) Pub Date : 2020-03-11 , DOI: 10.1016/j.immuni.2020.02.002 Long Shuang Huang 1 , Zhigang Hong 1 , Wei Wu 2 , Shiqin Xiong 1 , Ming Zhong 2 , Xiaopei Gao 1 , Jalees Rehman 3 , Asrar B Malik 1
Affiliation
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Cytosolic DNA acts as a universal danger-associated molecular pattern (DAMP) signal; however, the mechanisms of self-DNA release into the cytosol and its role in inflammatory tissue injury are not well understood. We found that the internalized bacterial endotoxin lipopolysaccharide (LPS) activated the pore-forming protein Gasdermin D, which formed mitochondrial pores and induced mitochondrial DNA (mtDNA) release into the cytosol of endothelial cells. mtDNA was recognized by the DNA sensor cGAS and generated the second messenger cGAMP, which suppressed endothelial cell proliferation by downregulating YAP1 signaling. This indicated that the surviving endothelial cells in the penumbrium of the inflammatory injury were compromised in their regenerative capacity. In an experimental model of inflammatory lung injury, deletion of cGas in mice restored endothelial regeneration. The results suggest that targeting the endothelial Gasdermin D activated cGAS-YAP signaling pathway could serve as a potential strategy for restoring endothelial function after inflammatory injury.
中文翻译：
mtDNA激活cGAS信号传导并抑制YAP介导的内皮细胞增殖程序，以促进炎性损伤。
胞质DNA充当普遍危险相关分子模式（DAMP）信号；然而，人们对自我DNA释放到胞质溶胶中的机制及其在炎性组织损伤中的作用尚不十分了解。我们发现内在化细菌内毒素脂多糖（LPS）激活了成孔蛋白Gasdermin D，后者形成了线粒体孔并诱导线粒体DNA（mtDNA）释放到内皮细胞的细胞质中。mtDNA被DNA传感器cGAS识别并生成第二个信使cGAMP，该信使通过下调YAP1信号传导抑制了内皮细胞的增殖。这表明炎性损伤半影中存活的内皮细胞的再生能力受到损害。在炎症性肺损伤的实验模型中，小鼠中cGas的缺失恢复了内皮再生。结果表明，靶向内皮Gastermin D激活的cGAS-YAP信号通路可以作为炎症损伤后恢复内皮功能的潜在策略。
更新日期：2020-03-12
中文翻译：
mtDNA激活cGAS信号传导并抑制YAP介导的内皮细胞增殖程序，以促进炎性损伤。
胞质DNA充当普遍危险相关分子模式（DAMP）信号；然而，人们对自我DNA释放到胞质溶胶中的机制及其在炎性组织损伤中的作用尚不十分了解。我们发现内在化细菌内毒素脂多糖（LPS）激活了成孔蛋白Gasdermin D，后者形成了线粒体孔并诱导线粒体DNA（mtDNA）释放到内皮细胞的细胞质中。mtDNA被DNA传感器cGAS识别并生成第二个信使cGAMP，该信使通过下调YAP1信号传导抑制了内皮细胞的增殖。这表明炎性损伤半影中存活的内皮细胞的再生能力受到损害。在炎症性肺损伤的实验模型中，小鼠中cGas的缺失恢复了内皮再生。结果表明，靶向内皮Gastermin D激活的cGAS-YAP信号通路可以作为炎症损伤后恢复内皮功能的潜在策略。
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