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. 2021 May 20;12(1):50–75. doi: 10.1016/j.apsb.2021.05.011

Figure 5.

Figure 5

The DNA-sensing cGAS–STING pathway activation-induces endothelial and vascular dysfunction. Metabolic stress-mediated upregulation of free fatty acids and the cytosolic accumulation of LPS triggers mitochondria damage. These actions destabilize mtDNA compartmentalization and promote mtDNA release into endothelial cytosol. In turn, the mtDNA is sensed by cGAS, which subsequently activates the STING–TBK-1 pathway, leading to the phosphorylation of IRF3 and LATS1/2. Active IRF3 translocate to the nucleus to promote transcription expression of ICAM1, MST1, and cytokines, including IFN-I. Expressed MST1 together with activated STING–TBK-1 function to suppress the Hippo pathway by stimulating phosphorylation of LATS1/2. This represses cyclin D-mediated endothelial cell proliferation and vascular repair. In addition, mutations in the STING-encoding gene can directly induce endothelial dysfunction through the progressive stimulation of endothelial activation and adhesion molecules, pro-inflammatory cytokines and factors, endothelial cell-death, etc., to drive pathological vascular conditions in SAVI patients.