Cargando…

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

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)...

Descripción completa

Detalles Bibliográficos
Autores principales: Morehouse, Benjamin R., Yip, Matthew C. J., Keszei, Alexander F. A., McNamara-Bordewick, Nora K., Shao, Sichen, Kranzusch, Philip J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402430/
https://www.ncbi.nlm.nih.gov/pubmed/35859168
http://dx.doi.org/10.1038/s41586-022-04999-1
_version_ 1784773174983917568
author Morehouse, Benjamin R.
Yip, Matthew C. J.
Keszei, Alexander F. A.
McNamara-Bordewick, Nora K.
Shao, Sichen
Kranzusch, Philip J.
author_facet Morehouse, Benjamin R.
Yip, Matthew C. J.
Keszei, Alexander F. A.
McNamara-Bordewick, Nora K.
Shao, Sichen
Kranzusch, Philip J.
author_sort Morehouse, Benjamin R.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9402430
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-94024302022-08-26 Cryo-EM structure of an active bacterial TIR–STING filament complex Morehouse, Benjamin R. Yip, Matthew C. J. Keszei, Alexander F. A. McNamara-Bordewick, Nora K. Shao, Sichen Kranzusch, Philip J. Nature Article 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. Nature Publishing Group UK 2022-07-20 2022 /pmc/articles/PMC9402430/ /pubmed/35859168 http://dx.doi.org/10.1038/s41586-022-04999-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Morehouse, Benjamin R.
Yip, Matthew C. J.
Keszei, Alexander F. A.
McNamara-Bordewick, Nora K.
Shao, Sichen
Kranzusch, Philip J.
Cryo-EM structure of an active bacterial TIR–STING filament complex
title Cryo-EM structure of an active bacterial TIR–STING filament complex
title_full Cryo-EM structure of an active bacterial TIR–STING filament complex
title_fullStr Cryo-EM structure of an active bacterial TIR–STING filament complex
title_full_unstemmed Cryo-EM structure of an active bacterial TIR–STING filament complex
title_short Cryo-EM structure of an active bacterial TIR–STING filament complex
title_sort cryo-em structure of an active bacterial tir–sting filament complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402430/
https://www.ncbi.nlm.nih.gov/pubmed/35859168
http://dx.doi.org/10.1038/s41586-022-04999-1
work_keys_str_mv AT morehousebenjaminr cryoemstructureofanactivebacterialtirstingfilamentcomplex
AT yipmatthewcj cryoemstructureofanactivebacterialtirstingfilamentcomplex
AT keszeialexanderfa cryoemstructureofanactivebacterialtirstingfilamentcomplex
AT mcnamarabordewicknorak cryoemstructureofanactivebacterialtirstingfilamentcomplex
AT shaosichen cryoemstructureofanactivebacterialtirstingfilamentcomplex
AT kranzuschphilipj cryoemstructureofanactivebacterialtirstingfilamentcomplex