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STING cyclic dinucleotide sensing originated in bacteria
Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides released during bacterial infection and endogenous cyclic GMP–AMP signaling during viral infection and antitumor immunity(1–5). STING shares no structural homology with other known signaling...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572726/ https://www.ncbi.nlm.nih.gov/pubmed/32877915 http://dx.doi.org/10.1038/s41586-020-2719-5 |
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author | Morehouse, Benjamin R. Govande, Apurva A. Millman, Adi Keszei, Alexander F.A. Lowey, Brianna Ofir, Gal Shao, Sichen Sorek, Rotem Kranzusch, Philip J. |
author_facet | Morehouse, Benjamin R. Govande, Apurva A. Millman, Adi Keszei, Alexander F.A. Lowey, Brianna Ofir, Gal Shao, Sichen Sorek, Rotem Kranzusch, Philip J. |
author_sort | Morehouse, Benjamin R. |
collection | PubMed |
description | Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides released during bacterial infection and endogenous cyclic GMP–AMP signaling during viral infection and antitumor immunity(1–5). STING shares no structural homology with other known signaling proteins(6–9), limiting functional analysis and preventing explanation for the origin of cyclic dinucleotide signaling in mammalian innate immunity. Here we discover functional STING homologues encoded within prokaryotic defense islands and reveal a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to c-di-GMP synthesized by a neighboring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple cyclic dinucleotide recognition with protein filament formation to drive TIR effector domain oligomerization and rapid NAD(+) cleavage. We reconstruct the evolutionary events following acquisition of STING into metazoan innate immunity and determine the structure of a full-length TIR-STING fusion from the Pacific oyster C. gigas. Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signaling and reveal conservation of a functional cGAS-STING pathway in prokaryotic bacteriophage defense. |
format | Online Article Text |
id | pubmed-7572726 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-75727262021-03-02 STING cyclic dinucleotide sensing originated in bacteria Morehouse, Benjamin R. Govande, Apurva A. Millman, Adi Keszei, Alexander F.A. Lowey, Brianna Ofir, Gal Shao, Sichen Sorek, Rotem Kranzusch, Philip J. Nature Article Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides released during bacterial infection and endogenous cyclic GMP–AMP signaling during viral infection and antitumor immunity(1–5). STING shares no structural homology with other known signaling proteins(6–9), limiting functional analysis and preventing explanation for the origin of cyclic dinucleotide signaling in mammalian innate immunity. Here we discover functional STING homologues encoded within prokaryotic defense islands and reveal a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to c-di-GMP synthesized by a neighboring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple cyclic dinucleotide recognition with protein filament formation to drive TIR effector domain oligomerization and rapid NAD(+) cleavage. We reconstruct the evolutionary events following acquisition of STING into metazoan innate immunity and determine the structure of a full-length TIR-STING fusion from the Pacific oyster C. gigas. Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signaling and reveal conservation of a functional cGAS-STING pathway in prokaryotic bacteriophage defense. 2020-09-02 2020-10 /pmc/articles/PMC7572726/ /pubmed/32877915 http://dx.doi.org/10.1038/s41586-020-2719-5 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Morehouse, Benjamin R. Govande, Apurva A. Millman, Adi Keszei, Alexander F.A. Lowey, Brianna Ofir, Gal Shao, Sichen Sorek, Rotem Kranzusch, Philip J. STING cyclic dinucleotide sensing originated in bacteria |
title | STING cyclic dinucleotide sensing originated in bacteria |
title_full | STING cyclic dinucleotide sensing originated in bacteria |
title_fullStr | STING cyclic dinucleotide sensing originated in bacteria |
title_full_unstemmed | STING cyclic dinucleotide sensing originated in bacteria |
title_short | STING cyclic dinucleotide sensing originated in bacteria |
title_sort | sting cyclic dinucleotide sensing originated in bacteria |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572726/ https://www.ncbi.nlm.nih.gov/pubmed/32877915 http://dx.doi.org/10.1038/s41586-020-2719-5 |
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