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

Inflammation Mice, Knockout 0301 basic medicine 0303 health sciences 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
DOI: 10.1016/j.immuni.2020.02.002 Publication Date: 2020-03-11T16:43:44Z
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 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.
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