Fig. 1: Overview of the cGAS–STING signalling pathway.

A schematic detailing double-stranded DNA (dsDNA)-induced activation of cytosolic cyclic GMP–AMP synthase (cGAS), which can occur through pathogen infection or cellular stress. On binding dsDNA, cGAS dimers assemble on dsDNA resulting in enzymatic activation of cGAS and synthesis of 2′3′ cyclic GMP–AMP (cGAMP). cGAMP binds to stimulator of interferon genes (STING) dimers localized at the endoplasmic reticulum (ER) membrane, which leads to profound conformational changes that trigger STING oligomerization, liberation from anchoring factors (such as STIM1), interaction with trafficking factors (for example, SEC24/23, STEEP, not depicted in figure) and, finally, incorporation into coatomer protein complex II (COPII) vesicles. On passing through the ER–Golgi intermediate compartment (ERGIC) and Golgi, STING recruits TANK-binding kinase 1 (TBK1), promoting TBK1 autophosphorylation, STING phosphorylation at Ser366 and recruitment of interferon regulatory factor 3 (IRF3). The phosphorylation of IRF3 by TBK1 enables IRF3 dimerization and translocation to the nucleus to induce gene expression of type I interferons, interferon-stimulated genes (ISGs), and several other inflammatory mediators, pro-apoptotic genes and chemokines. Activation of STING also leads to NF-κB activation and the formation of LC3⁺ vesicles (autophagosomes) by a non-canonical mechanism of autophagy. In the end, both STING within autophagosomes and STING from the Golgi traffic to the lysosome, where STING degradation occurs. Steady-state STING translocation through the secretory pathway in the absence of robust cGAMP stimulation is counteracted by continuous retrograde transport to the ER, a step that is mediated by COPI vesicles and facilitated by an interaction of STING with SURF4.