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C-terminal domain of metazoan Stimulator Of Interferon Genes (STING) protein, bacterial STING, and similar proteins This model represents the cytoplasmic ligand-binding domain (LBD, or cyclic-dinucleotide-binding domain) of Stimulator Of Interferon Genes (STING) protein, also called transmembrane protein 173 (TMEM173), mediator of IRF3 activation (MITA), endoplasmic reticulum IFN stimulator (ERIS), or N-terminal methionine-proline-tyrosine-serine plasma membrane tetraspanner (MYSA) of metazoa, as well as STING proteins in bacteria. STING is a receptor that senses foreign cyclic dinucleotides that are released during bacterial infections as well as in endogenous cyclic GMP-AMP (cGAMP) signaling during viral infection and anti-tumor immunity. STING activates downstream transcription factor IRF3 (interferon regulatory factor 3) and STAT (signal transducer and activator of transcription) via TBK1 ((Tank binding kinase 1), which are responsible for antiviral and innate immune response against intracellular pathogens. STING's activation of IRF3 and STAT induces the production of type 1 interferon and target genes involved in immune cell homing such as chemokines, respectively. STING may also function as a direct cytosolic DNA sensor. STING also has a role in B cell adaptive immunity through modulating B cell receptor signaling via PI3K (phosphatidylinositol 3-kinase). STING is encoded by the STING1 gene in mammals. It is an endoplasmic reticulum (ER) membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signaling domain. The cytoplasmic domain forms a homodimer, which undergoes conformational changes upon binding to cGAMP. Bacterial STING proteins are functional cyclic dinucleotide receptors and define a minimal homodimeric scaffold that selectively responds to cyclic di-GMP. They couple the recognition of cyclic dinucleotides with the formation of protein filaments to drive oligomerization of TIR effector domains and rapid NAD+ cleavage. Bacterial STING occurs primarily as a fusion to a Toll/interleukin-1 receptor (TIR, or Toll and IL-1 receptor) adaptor domain; TIR domains can function as beta-nicotinamide adenine dinucleotide (NAD+) hydrolases in plant and animal immunity. Bacterial STING homologs are 20% smaller and markedly compact, such that the metazoan insertions into the core bacterial fold are necessary for induction of autophagy, and the C-terminal tail contains motifs for the recruitment of kinases and transcription factors in vertebrates. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",