Fig. 2.

cGAS/STING (cGLR) signaling-dependent IR. cGLRs or cGAS/STING signaling is critical for recognizing the cytosolic dsDNA and generating type 1 IFNs and NF-κB-dependent cytokines. cGAS-mediated cytosolic dsDNA recognition by cGAS generates cGAMP. STING recognizes cGAMP and undergoes dimerization to become active. The activated STING activates TBK1 and TRAF6, which activate IRF3 and NF-κB-dependent type 1 IFNs and cytokines. This process also activates glycolysis by increasing mtROS production, succinate accumulation, and HIF-α stabilization. The increased glycolysis overproduces ATP molecules, which further increases STING activation. Furthermore, TLR activation induced mtROS production and mitochondrial damage, releasing the mitochondrial DNA into the cytosol that the cGAS recognizes to initiate the cGAS/STING signaling. Hence, TLR and cGAS/STING signaling support each other through IR or glycolysis.