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
AUTHORS (8)
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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