Unveiling the Binding Mode between Bacterial STING & c-di-GMP

Upon identifying two complex crystal structures of bacterial STING/c-di-GMP, this study reveals the precise binding mode of c-di-GMP to the bacterial STING. The findings clarify how bacterial STING differentiates c-di-GMP second messengers from other cyclic dinucleotides during viral infections. Besides that, the interaction between bacterial STING and c-di-GMP is found to be accountable for the oligomerization of the former into long filament. According to the oligomerization mechanism and ligand specificity, the bacterial STING is categorized into Class I and II. Since mammalian STING protein originated in bacteria, the output of this study provides valuable insights in the innate immunity of human.

Stimulator of interferon gene (STING) is a crucial immune sensor which, during viral infection, triggers self-destruction of infected cells in order to contain the infection. Although the signaling pathway is initiated by the binding between STING and c-di-GMP, the exact binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism remain vague. Thus, this study is carried out to investigate the mechanism by determining the crystal structures of bacterial STING/c-di-GMP. It also proposes that Class II bacterial STING, which recognizes 3’3’-cGAMP more favorably, is in the evolutionary transition from c-di-GMP-dependent signaling in bacteria to 2’3’-cGAMP-dependent signaling in eukaryotes. Other than facilitating future STING-related studies, this research complements the existing knowledge base for human’s innate immune signaling.

STING plays an important role in innate immunity as an essential mediator and inducer. Thus, to speed up the advance of research related to human immune system, a more in-depth understanding of mammalian STING protein (which originated in bacteria) is required. By shedding light on the crucial mechanisms involved in human immune system, this study fulfils UNSDG 3: Good Health & Well-Being.