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

• DOI: 10.1016/j.immuni.2020.02.002
• Publication Date: 2020-03-11T16:43:44Z
• Authors: Long Shuang Huang; Zhigang Hong; Wei Wu; Shiqin Xiong; Ming Zhong; Xiaopei Gao; Jalees Rehman; Asrar B. Malik
• Keywords: Inflammation; Mice, Knockout; 0301 basic medicine; Intracellular Signaling Peptides and Proteins; Endothelial Cells; Membrane Proteins; Cell Cycle Proteins; YAP-Signaling Proteins; Phosphate-Binding Proteins; DNA, Mitochondrial; Nucleotidyltransferases; Mice, Inbred C57BL; 03 medical and health sciences; Cytosol; HEK293 Cells; Animals; Humans; Nucleotides, Cyclic; Cells, Cultured; Adaptor Proteins, Signal Transducing; Cell Proliferation; Signal Transduction

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.