Cryo-EM structure of an active bacterial TIR-STING filament complex.

Abstract

Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes1-4. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide4-13, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)-STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR-STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals5. The active bacterial TIR-STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD+ hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.

• Authors: Benjamin R Morehouse, Matthew C J Yip, Alexander F A Keszei, Nora K McNamara-Bordewick, Sichen Shao, Philip J Kranzusch
• Journal: Nature (Nature) Vol. 608 Issue 7924 Pg. 803-807 (08 2022) ISSN: 1476-4687 [Electronic] England
• PMID: 35859168 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antiviral Agents
• Bacterial Proteins
• Dinucleoside Phosphates
• Membrane Proteins
• Receptors, Interleukin-1
• Toll-Like Receptors

Topics

• Animals
• Antiviral Agents (metabolism)
• Bacterial Proteins (chemistry, immunology, metabolism, ultrastructure)
• Bacteriophages (immunology)
• Cryoelectron Microscopy
• Dinucleoside Phosphates (metabolism)
• Humans
• Immunity, Innate
• Membrane Proteins (chemistry, immunology, metabolism, ultrastructure)
• Operon (genetics)
• Receptors, Interleukin-1 (chemistry, immunology, metabolism, ultrastructure)
• Sphingobacterium (chemistry, genetics, ultrastructure, virology)
• Toll-Like Receptors (chemistry, immunology, metabolism, ultrastructure)