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 –...
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| Veröffentlicht in: | Nature (London) 2022-08, Vol.608 (7924), p.803-807 |
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| creator | Morehouse, Benjamin R. Yip, Matthew C. J. Keszei, Alexander F. A. McNamara-Bordewick, Nora K. Shao, Sichen Kranzusch, Philip J. |
| 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.
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined. |
| doi_str_mv | 10.1038/s41586-022-04999-1 |
| format | Article |
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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.
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-022-04999-1</identifier><identifier>PMID: 35859168</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/28 ; 631/250/262 ; 631/326/41/2533 ; 631/45/607/1164 ; 631/45/612/1233 ; 631/535/1258/1259 ; 82/80 ; 82/83 ; Animals ; Antiviral Agents - metabolism ; Assembly ; Bacteria ; Bacterial Proteins - chemistry ; Bacterial Proteins - immunology ; Bacterial Proteins - metabolism ; Bacterial Proteins - ultrastructure ; Bacteriophages - immunology ; Cryoelectron Microscopy ; Dinucleoside Phosphates - metabolism ; Electron microscopy ; Humanities and Social Sciences ; Humans ; Immunity, Innate ; Innate immunity ; Interfaces ; Interferon ; Interleukin 1 ; Ligands ; Membrane Proteins - chemistry ; Membrane Proteins - immunology ; Membrane Proteins - metabolism ; Membrane Proteins - ultrastructure ; Microscopy ; multidisciplinary ; Oligonucleotides ; Operon - genetics ; Phages ; Proteins ; Receptors, Interleukin-1 - chemistry ; Receptors, Interleukin-1 - immunology ; Receptors, Interleukin-1 - metabolism ; Receptors, Interleukin-1 - ultrastructure ; Science ; Science (multidisciplinary) ; Signalling systems ; Sphingobacterium - chemistry ; Sphingobacterium - genetics ; Sphingobacterium - ultrastructure ; Sphingobacterium - virology ; Stimulators ; Toll-Like Receptors - chemistry ; Toll-Like Receptors - immunology ; Toll-Like Receptors - metabolism ; Toll-Like Receptors - ultrastructure</subject><ispartof>Nature (London), 2022-08, Vol.608 (7924), p.803-807</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>Copyright Nature Publishing Group Aug 25, 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-1ef120615f4dd95042f661c9cc926db70c12e40fd9592bd70955280aaec6324b3</citedby><cites>FETCH-LOGICAL-c474t-1ef120615f4dd95042f661c9cc926db70c12e40fd9592bd70955280aaec6324b3</cites><orcidid>0000-0002-8524-7998 ; 0000-0003-3352-5463 ; 0000-0002-2505-9987 ; 0000-0002-4943-733X ; 0000-0003-2679-5537</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-022-04999-1$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-022-04999-1$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35859168$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morehouse, Benjamin R.</creatorcontrib><creatorcontrib>Yip, Matthew C. J.</creatorcontrib><creatorcontrib>Keszei, Alexander F. A.</creatorcontrib><creatorcontrib>McNamara-Bordewick, Nora K.</creatorcontrib><creatorcontrib>Shao, Sichen</creatorcontrib><creatorcontrib>Kranzusch, Philip J.</creatorcontrib><title>Cryo-EM structure of an active bacterial TIR–STING filament complex</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><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.
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.</description><subject>101/28</subject><subject>631/250/262</subject><subject>631/326/41/2533</subject><subject>631/45/607/1164</subject><subject>631/45/612/1233</subject><subject>631/535/1258/1259</subject><subject>82/80</subject><subject>82/83</subject><subject>Animals</subject><subject>Antiviral Agents - metabolism</subject><subject>Assembly</subject><subject>Bacteria</subject><subject>Bacterial Proteins - chemistry</subject><subject>Bacterial Proteins - immunology</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bacterial Proteins - ultrastructure</subject><subject>Bacteriophages - immunology</subject><subject>Cryoelectron Microscopy</subject><subject>Dinucleoside Phosphates - metabolism</subject><subject>Electron microscopy</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>Innate immunity</subject><subject>Interfaces</subject><subject>Interferon</subject><subject>Interleukin 1</subject><subject>Ligands</subject><subject>Membrane Proteins - chemistry</subject><subject>Membrane Proteins - immunology</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Proteins - ultrastructure</subject><subject>Microscopy</subject><subject>multidisciplinary</subject><subject>Oligonucleotides</subject><subject>Operon - genetics</subject><subject>Phages</subject><subject>Proteins</subject><subject>Receptors, Interleukin-1 - chemistry</subject><subject>Receptors, Interleukin-1 - immunology</subject><subject>Receptors, Interleukin-1 - metabolism</subject><subject>Receptors, Interleukin-1 - ultrastructure</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signalling systems</subject><subject>Sphingobacterium - chemistry</subject><subject>Sphingobacterium - genetics</subject><subject>Sphingobacterium - ultrastructure</subject><subject>Sphingobacterium - virology</subject><subject>Stimulators</subject><subject>Toll-Like Receptors - chemistry</subject><subject>Toll-Like Receptors - immunology</subject><subject>Toll-Like Receptors - metabolism</subject><subject>Toll-Like Receptors - ultrastructure</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kc1u1DAUhS0EotPCC7CoIrFh43J94594UwmNhnakAhIMa8txnJIqiQc7qeiOd-gb9klwmdIWFqzu4nz33J9DyCsGRwzK6m3iTFSSAiIFrrWm7AlZMK4k5bJST8kCACsKVSn3yH5KFwAgmOLPyV4pKqGZrBZktYxXga4-FGmKs5vm6IvQFnYsrJu6S1_UufrY2b7YrD_f_Lz-sll_PCnarreDH6fChWHb-x8vyLPW9sm_vKsH5Ov71WZ5Ss8-nayX786o44pPlPmWIUgmWt40WgDHVkrmtHMaZVMrcAw9hzZrGutGgRYCK7DWO1kir8sDcrzz3c714BuXV4i2N9vYDTZemWA787cydt_Mebg0mgPyErLBmzuDGL7PPk1m6JLzfW9HH-ZkUGpUQqHiGX39D3oR5jjm8wwqUCjyozFTuKNcDClF394vw8DcpmR2KZmckvmdkmG56fDxGfctf2LJQLkDUpbGcx8fZv_H9he4xZ0m</recordid><startdate>20220825</startdate><enddate>20220825</enddate><creator>Morehouse, Benjamin R.</creator><creator>Yip, Matthew C. 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J. ; Keszei, Alexander F. A. ; McNamara-Bordewick, Nora K. ; Shao, Sichen ; Kranzusch, Philip J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-1ef120615f4dd95042f661c9cc926db70c12e40fd9592bd70955280aaec6324b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>101/28</topic><topic>631/250/262</topic><topic>631/326/41/2533</topic><topic>631/45/607/1164</topic><topic>631/45/612/1233</topic><topic>631/535/1258/1259</topic><topic>82/80</topic><topic>82/83</topic><topic>Animals</topic><topic>Antiviral Agents - metabolism</topic><topic>Assembly</topic><topic>Bacteria</topic><topic>Bacterial Proteins - chemistry</topic><topic>Bacterial Proteins - immunology</topic><topic>Bacterial Proteins - metabolism</topic><topic>Bacterial Proteins - ultrastructure</topic><topic>Bacteriophages - immunology</topic><topic>Cryoelectron Microscopy</topic><topic>Dinucleoside Phosphates - metabolism</topic><topic>Electron microscopy</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>Innate immunity</topic><topic>Interfaces</topic><topic>Interferon</topic><topic>Interleukin 1</topic><topic>Ligands</topic><topic>Membrane Proteins - chemistry</topic><topic>Membrane Proteins - immunology</topic><topic>Membrane Proteins - metabolism</topic><topic>Membrane Proteins - ultrastructure</topic><topic>Microscopy</topic><topic>multidisciplinary</topic><topic>Oligonucleotides</topic><topic>Operon - genetics</topic><topic>Phages</topic><topic>Proteins</topic><topic>Receptors, Interleukin-1 - chemistry</topic><topic>Receptors, Interleukin-1 - immunology</topic><topic>Receptors, Interleukin-1 - metabolism</topic><topic>Receptors, Interleukin-1 - ultrastructure</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signalling systems</topic><topic>Sphingobacterium - chemistry</topic><topic>Sphingobacterium - genetics</topic><topic>Sphingobacterium - ultrastructure</topic><topic>Sphingobacterium - virology</topic><topic>Stimulators</topic><topic>Toll-Like Receptors - chemistry</topic><topic>Toll-Like Receptors - immunology</topic><topic>Toll-Like Receptors - metabolism</topic><topic>Toll-Like Receptors - ultrastructure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morehouse, Benjamin R.</creatorcontrib><creatorcontrib>Yip, Matthew C. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morehouse, Benjamin R.</au><au>Yip, Matthew C. J.</au><au>Keszei, Alexander F. A.</au><au>McNamara-Bordewick, Nora K.</au><au>Shao, Sichen</au><au>Kranzusch, Philip J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cryo-EM structure of an active bacterial TIR–STING filament complex</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2022-08-25</date><risdate>2022</risdate><volume>608</volume><issue>7924</issue><spage>803</spage><epage>807</epage><pages>803-807</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><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 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.
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>35859168</pmid><doi>10.1038/s41586-022-04999-1</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-8524-7998</orcidid><orcidid>https://orcid.org/0000-0003-3352-5463</orcidid><orcidid>https://orcid.org/0000-0002-2505-9987</orcidid><orcidid>https://orcid.org/0000-0002-4943-733X</orcidid><orcidid>https://orcid.org/0000-0003-2679-5537</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2022-08, Vol.608 (7924), p.803-807 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9402430 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 101/28 631/250/262 631/326/41/2533 631/45/607/1164 631/45/612/1233 631/535/1258/1259 82/80 82/83 Animals Antiviral Agents - metabolism Assembly Bacteria Bacterial Proteins - chemistry Bacterial Proteins - immunology Bacterial Proteins - metabolism Bacterial Proteins - ultrastructure Bacteriophages - immunology Cryoelectron Microscopy Dinucleoside Phosphates - metabolism Electron microscopy Humanities and Social Sciences Humans Immunity, Innate Innate immunity Interfaces Interferon Interleukin 1 Ligands Membrane Proteins - chemistry Membrane Proteins - immunology Membrane Proteins - metabolism Membrane Proteins - ultrastructure Microscopy multidisciplinary Oligonucleotides Operon - genetics Phages Proteins Receptors, Interleukin-1 - chemistry Receptors, Interleukin-1 - immunology Receptors, Interleukin-1 - metabolism Receptors, Interleukin-1 - ultrastructure Science Science (multidisciplinary) Signalling systems Sphingobacterium - chemistry Sphingobacterium - genetics Sphingobacterium - ultrastructure Sphingobacterium - virology Stimulators Toll-Like Receptors - chemistry Toll-Like Receptors - immunology Toll-Like Receptors - metabolism Toll-Like Receptors - ultrastructure |
| title | Cryo-EM structure of an active bacterial TIR–STING filament complex |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T05%3A34%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cryo-EM%20structure%20of%20an%20active%20bacterial%20TIR%E2%80%93STING%20filament%20complex&rft.jtitle=Nature%20(London)&rft.au=Morehouse,%20Benjamin%20R.&rft.date=2022-08-25&rft.volume=608&rft.issue=7924&rft.spage=803&rft.epage=807&rft.pages=803-807&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-022-04999-1&rft_dat=%3Cproquest_pubme%3E2707254762%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2707254762&rft_id=info:pmid/35859168&rfr_iscdi=true |