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Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence
cGAS is an evolutionarily conserved enzyme that has a pivotal role in immune defence against infection(1–3). In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP–AMP (cGAMP)(4,5), which leads to the expression of antimicrobial genes(6,7). In bacteria, cyclic dinucleotide (CDN)-based...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097602/ https://www.ncbi.nlm.nih.gov/pubmed/36848932 http://dx.doi.org/10.1038/s41586-023-05862-7 |
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author | Jenson, Justin M. Li, Tuo Du, Fenghe Ea, Chee-Kwee Chen, Zhijian J. |
author_facet | Jenson, Justin M. Li, Tuo Du, Fenghe Ea, Chee-Kwee Chen, Zhijian J. |
author_sort | Jenson, Justin M. |
collection | PubMed |
description | cGAS is an evolutionarily conserved enzyme that has a pivotal role in immune defence against infection(1–3). In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP–AMP (cGAMP)(4,5), which leads to the expression of antimicrobial genes(6,7). In bacteria, cyclic dinucleotide (CDN)-based anti-phage signalling systems (CBASS) have been discovered(8–11). These systems are composed of cGAS-like enzymes and various effector proteins that kill bacteria on phage infection, thereby stopping phage spread. Of the CBASS systems reported, approximately 39% contain Cap2 and Cap3, which encode proteins with homology to ubiquitin conjugating (E1/E2) and deconjugating enzymes, respectively(8,12). Although these proteins are required to prevent infection of some bacteriophages(8), the mechanism by which the enzymatic activities exert an anti-phage effect is unknown. Here we show that Cap2 forms a thioester bond with the C-terminal glycine of cGAS and promotes conjugation of cGAS to target proteins in a process that resembles ubiquitin conjugation. The covalent conjugation of cGAS increases the production of cGAMP. Using a genetic screen, we found that the phage protein Vs.4 antagonized cGAS signalling by binding tightly to cGAMP (dissociation constant of approximately 30 nM) and sequestering it. A crystal structure of Vs.4 bound to cGAMP showed that Vs.4 formed a hexamer that was bound to three molecules of cGAMP. These results reveal a ubiquitin-like conjugation mechanism that regulates cGAS activity in bacteria and illustrates an arms race between bacteria and viruses through controlling CDN levels. |
format | Online Article Text |
id | pubmed-10097602 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100976022023-04-14 Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence Jenson, Justin M. Li, Tuo Du, Fenghe Ea, Chee-Kwee Chen, Zhijian J. Nature Article cGAS is an evolutionarily conserved enzyme that has a pivotal role in immune defence against infection(1–3). In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP–AMP (cGAMP)(4,5), which leads to the expression of antimicrobial genes(6,7). In bacteria, cyclic dinucleotide (CDN)-based anti-phage signalling systems (CBASS) have been discovered(8–11). These systems are composed of cGAS-like enzymes and various effector proteins that kill bacteria on phage infection, thereby stopping phage spread. Of the CBASS systems reported, approximately 39% contain Cap2 and Cap3, which encode proteins with homology to ubiquitin conjugating (E1/E2) and deconjugating enzymes, respectively(8,12). Although these proteins are required to prevent infection of some bacteriophages(8), the mechanism by which the enzymatic activities exert an anti-phage effect is unknown. Here we show that Cap2 forms a thioester bond with the C-terminal glycine of cGAS and promotes conjugation of cGAS to target proteins in a process that resembles ubiquitin conjugation. The covalent conjugation of cGAS increases the production of cGAMP. Using a genetic screen, we found that the phage protein Vs.4 antagonized cGAS signalling by binding tightly to cGAMP (dissociation constant of approximately 30 nM) and sequestering it. A crystal structure of Vs.4 bound to cGAMP showed that Vs.4 formed a hexamer that was bound to three molecules of cGAMP. These results reveal a ubiquitin-like conjugation mechanism that regulates cGAS activity in bacteria and illustrates an arms race between bacteria and viruses through controlling CDN levels. Nature Publishing Group UK 2023-02-27 2023 /pmc/articles/PMC10097602/ /pubmed/36848932 http://dx.doi.org/10.1038/s41586-023-05862-7 Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Jenson, Justin M. Li, Tuo Du, Fenghe Ea, Chee-Kwee Chen, Zhijian J. Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence |
title | Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence |
title_full | Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence |
title_fullStr | Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence |
title_full_unstemmed | Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence |
title_short | Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence |
title_sort | ubiquitin-like conjugation by bacterial cgas enhances anti-phage defence |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097602/ https://www.ncbi.nlm.nih.gov/pubmed/36848932 http://dx.doi.org/10.1038/s41586-023-05862-7 |
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