Fig. 4

Negative regulation of STING-mediated response. STING-mediated signalling can be negatively regulated via multiple mechanisms, including E3 ubiquitin ligase TRIM30α- and TRIM21- mediated degradation of STING and its upstream DNA sensor DDX41, respectively. Certain phosphodiesterases (PDEs) also specifically hydrolyse bacterial cyclic dinucleotides to prevent them being sensed by STING. Akt kinase is also capable of inhibiting cGAS detection of cytoplasmic DNA. Activated cGAS produces 2′-3′ cGAMP to release AMPK-mediated inhibition of ULK1, which in turn blocks IRF3 recruitment downstream of STING activation. 2′-3′ cGAMP produced by cGAS can also activate Beclin-1 which can sequester cGAS as well as induce degradation of dsDNA. In a negative feedback loop, the product of the IRF3-dependent antiviral response, microRNA-576-3P (miR-576-3P), can prevent further STING activation. Some viruses can encode proteases or protein inhibitors to interfere in STING signalling, while others may enhance the activity of inflammasome complexes NLRC3 and NLRX1 to block STING/ TBK1 interaction