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

Immunity. 2020 Mar 17;52(3):475-486.e5. doi: 10.1016/j.immuni.2020.02.002. Epub 2020 Mar 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 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.

Keywords: Gasdermin D; YAP; cGAS; endothelial regeneration; inflammation; lung injury; mitochondrial DNA; pyroptosis; vascular injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / genetics*
  • Cells, Cultured
  • Cytosol / metabolism
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • HEK293 Cells
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / genetics*
  • Nucleotidyltransferases / metabolism
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism
  • Signal Transduction
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA, Mitochondrial
  • Gsdmd protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Phosphate-Binding Proteins
  • Sting1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Nucleotidyltransferases
  • cGAS protein, mouse