Regulation of cGAS and STING signaling during inflammation and infection

Abstract

Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well as fundamental cellular functions such as autophagy, senescence, and apoptosis. Mutations leading to constitutive activation of STING cause devastating human diseases. Thus, the cGAS-STING pathway is of great interest because of its role in diverse cellular processes and because of the potential therapeutic implications of targeting cGAS and STING. Here, we review molecular and cellular mechanisms of STING signaling, and we propose a framework for understanding the immunological and other cellular functions of STING in the context of disease.

Keywords: COPA syndrome; SAVI; STING; STING-associated vasculopathy with onset in infancy; autoimmunity; autoinflammation; autophagy; cGAS; interferon; signaling.

Figure 1

Cytosolic DNA activates the cGAS-STING pathway. Cytosolic dsDNA, including from viruses, bacteria, and mislocalized endogenous DNA, binds to cGAS. DNA-bound cGAS undergoes a conformational shift that triggers production of cGAMP. Dimeric STING binds to cGAMP and undergoes a conformational change, allowing recruitment of TBK and the phosphorylation of the transcription factors IRF3 and NF-κB. Phosphorylated IRF3 and NF-κB translocate to the nucleus where they facilitate the transcription of effector genes. cGAMP, cyclic GMP-AMP; IRF3, IFN regulatory factor-3; STING, Stimulator of interferon genes

Figure 2

cGAS dimers form a ladder-like structure on long dsDNA.A, cGAS binds to dsDNA, changing the conformation of the active site, enabling the conversion of ATP and GTP to cGAMP. Dimerization of cGAS to dsDNA stabilizes the active site. B, longer strands of dsDNA (>50 bp) can accommodate multiple cGAS dimers and are organized in a 2:2 ladder conformation. C, long strands of dsDNA can be organized into U-loops via chaperone proteins, allowing for cGAS dimers to stably bind. cGAMP, cyclic GMP-AMP.

Figure 3

STING is regulated by its subcellular localization. (1) Cytosolic DNA triggers cGAS to produce 2′3′-cGAMP, which in turn (2) activates STING at the ER. (3) Polymeric STING is sorted into COPII vesicles destined for the ERGIC or Golgi. (4) At the ERGIC, STING induces LC3 lipidation of the ERGIC membrane, which leads to the generation of an autophagosome that includes STING and other molecules such as cGAS. (5) STING is negatively regulated by its own degradation in the autophagolysosome. (6) Alternatively, STING accumulates in the cis-Golgi. (7) STING forms a signaling complex with TBK1 and IRF3 in the trans-Golgi and post-Golgi vesicles. (8) STING can return from the cis-Golgi to the ER in COPI vesicles, or (9) the STING–TBK1–IRF3 signaling complex is fully formed at the trans-Golgi network. (10) The STING signaling complex is routed through endosomes and multivesicular bodies. (11) Lysosomal targeting of the STING signaling pathway results in its degradation after signaling and trafficking through the Golgi and into post-Golgi vesicles. cGAMP, cyclic GMP-AMP; ERGIC, ER–Golgi intermediate complex; IRF3, IFN regulatory factor-3; STING, Stimulator of interferon genes; TBK1, TANK-binding kinase-1.

Figure 4

Diverse mechanisms of viral subversion of cGAS-STING signaling. Both DNA and RNA viruses have developed various and sometimes similar mechanisms to antagonize cGAS-STING signaling. Depicted is the cGAS-STING pathway with RNA and DNA viruses, as well as corresponding viral proteins which inhibit signaling at each stage of the pathway. STING, Stimulator of interferon genes.