Crystal structure and functional implication of bacterial STING

• Published in: Nature communications Vol. 13; no. 1; p. 26
• Main Authors: Ko, Tzu-Ping, Wang, Yu-Chuan, Yang, Chia-Shin, Hou, Mei-Hui, Chen, Chao-Jung, Chiu, Yi-Fang, Chen, Yeh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 631/326/41/2536; 631/45/535; 631/535/1266; 82/80; 82/83; Bacteria; Bacteria - metabolism; Conserved sequence; Crystal structure; Crystallography, X-Ray; Cyclic GMP - analogs & derivatives; Cyclic GMP - chemistry; Dinucleoside Phosphates; Eukaryotes; Humanities and Social Sciences; Humans; Immunity, Innate; Infections; Interferon; Interferons; Ligands; Membrane Proteins - chemistry; Membrane Proteins - genetics; multidisciplinary; Nucleotides; Nucleotidyltransferases - metabolism; Oligomerization; Oligonucleotides; Phages; Prevotella; Protein interaction; Proteins; Recognition; Science; Science (multidisciplinary); Signalling systems; Stimulators; Suicide
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26583-3

Mammalian innate immune sensor STING ( ST imulator of IN terferon G ene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase (cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in β-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2’3’-cGAMP-dependent signaling in eukaryotes. The bacterial Cyclic-oligonucleotide-Based Anti-phage Signaling System (CBASS) contains a CD-NTase that synthesizes cyclic di- and tri-nucleotides, and bacterial STING proteins recognize c-di-GMP generated by CD-NTase during phage infection and signal the infected bacteria to commit suicide. Here, the authors provide insights into the molecular basis for c-di-GMP recognition of bacterial STING proteins by determining two STING protein crystal structures with bound c-di-GMP from Prevotella corporis and Myroides sp . ZB35.