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

Autor: Morehouse BR; Department of Microbiology, Harvard Medical School, Boston, MA, USA.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Yip MCJ; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Keszei AFA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., McNamara-Bordewick NK; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Shao S; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. sichen_shao@hms.harvard.edu., Kranzusch PJ; Department of Microbiology, Harvard Medical School, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Aug; Vol. 608 (7924), pp. 803-807. Date of Electronic Publication: 2022 Jul 20.
DOI: 10.1038/s41586-022-04999-1
Abstrakt: Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes 1-4 . Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide 4-13 , 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 mammals 5 . 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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