Stimulator of interferon genes protein (STING) C-terminal domain (STING CTD)

The Stimulator of interferon genes protein (STING), specifically its C-terminal domain (CTD), serves as a critical signaling hub in the innate immune system (UniProt Q86WV6). Located primarily in the endoplasmic reticulum, STING is activated upon binding cyclic dinucleotides (CDNs), such as cyclic GMP-AMP (cGAMP), which are produced by the enzyme cGAS in response to cytosolic double-stranded DNA (PubMed: 23722159). The CTD contains the ligand-binding pocket and undergoes a significant conformational change from an "open" to a "closed" state upon binding, which is essential for its activation (PubMed: 30104374). This structural shift facilitates the translocation of STING to the Golgi apparatus and the recruitment of TANK-binding kinase 1 (TBK1) (PubMed: 18724357). Subsequent phosphorylation of the CTD tail recruits interferon regulatory factor 3 (IRF3), leading to the production of Type I interferons and pro-inflammatory cytokines. In oncology, STING agonists targeting the CTD are being investigated to enhance the immunogenicity of the tumor microenvironment (PubMed: 31048552). Conversely, overactivation of the STING pathway is linked to autoinflammatory conditions like STING-associated vasculopathy with onset in infancy (SAVI), making the CTD a target for both agonistic and antagonistic therapeutic strategies (PubMed: 25029442). Therapeutic challenges include managing systemic inflammation and potential T-cell exhaustion resulting from chronic or high-dose activation.

Other names

TMEM173MITAERISMPYSTransmembrane protein 173

Agonism of the C-terminal domain induces a conformational change that facilitates STING translocation, TBK1 recruitment, and IRF3-mediated transcription of Type I interferons (PubMed: 30104374).