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线粒体DNA激活cGAS信号并抑制YAP介导的内皮细胞增殖
作者:小柯机器人 发布时间:2020/3/22 20:53:23

美国伊利诺斯大学医学院Asrar B. Malik、Jalees Rehman等研究人员合作发现,线粒体DNA激活cGAS信号并抑制YAP介导的内皮细胞增殖程序,从而促进炎性损伤。2020年3月11日,《免疫》杂志在线发表了这一成果。

研究人员发现內吞的细菌内毒素脂多糖(LPS)能够激活打孔蛋白Gasdermin D,从而形成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,从而通过下调YAP1信号来抑制内皮细胞增殖。这表明炎性损伤中存活的内皮细胞再生能力受到损害。在炎性肺损伤的实验模型中,小鼠cGas的缺失恢复了内皮的再生。结果表明,靶向内皮Gastermin D激活的cGAS-YAP信号通路可作为炎症损伤后恢复内皮功能的潜在策略。
 
据悉,胞质DNA是通用的危险相关分子模式(DAMP)信号;然而,人们对自身DNA释放到细胞质中的机制及其在炎性组织损伤中的作用还不甚了解。
 
附:英文原文

Title: mtDNA Activates cGAS Signaling and Suppresses the YAP-Mediated Endothelial Cell Proliferation Program to Promote Inflammatory Injury

Author: Long Shuang Huang, Zhigang Hong, Wei Wu, Shiqin Xiong, Ming Zhong, Xiaopei Gao, Jalees Rehman, Asrar B. Malik

Issue&Volume: 2020-03-11

Abstract: 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 inflammatorytissue injury are not well understood. We found that the internalized bacterial endotoxinlipopolysaccharide (LPS) activated the pore-forming protein Gasdermin D, which formedmitochondrial pores and induced mitochondrial DNA (mtDNA) release into the cytosolof endothelial cells. mtDNA was recognized by the DNA sensor cGAS and generated thesecond messenger cGAMP, which suppressed endothelial cell proliferation by downregulatingYAP1 signaling. This indicated that the surviving endothelial cells in the penumbriumof the inflammatory injury were compromised in their regenerative capacity. In anexperimental model of inflammatory lung injury, deletion of cGas in mice restored endothelial regeneration. The results suggest that targeting theendothelial Gasdermin D activated cGAS-YAP signaling pathway could serve as a potentialstrategy for restoring endothelial function after inflammatory injury.

DOI: 10.1016/j.immuni.2020.02.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30073-X

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新if:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx