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Dissection of the molecular circuitry controlling virulence in Francisella tularensis
Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicit...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630020/ https://www.ncbi.nlm.nih.gov/pubmed/28864445 http://dx.doi.org/10.1101/gad.303701.117 |
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author | Cuthbert, Bonnie J. Ross, Wilma Rohlfing, Amy E. Dove, Simon L. Gourse, Richard L. Brennan, Richard G. Schumacher, Maria A. |
author_facet | Cuthbert, Bonnie J. Ross, Wilma Rohlfing, Amy E. Dove, Simon L. Gourse, Richard L. Brennan, Richard G. Schumacher, Maria A. |
author_sort | Cuthbert, Bonnie J. |
collection | PubMed |
description | Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators—the heteromeric macrophage growth locus protein A (MglA)–stringent starvation protein A (SspA) complex and the DNA-binding protein pathogenicity island gene regulator (PigR)—activates FPI transcription and thus is essential for virulence. Intriguingly, the second messenger, guanosine–tetraphosphate (ppGpp), which is produced during infection, is also involved in coordinating Francisella virulence; however, its role has been unclear. Here we identify MglA–SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA–SspA. We demonstrate that MglA–SspA, which binds RNA polymerase (RNAP), also interacts with the C-terminal domain of PigR, thus anchoring the (MglA–SspA)–RNAP complex to the FPI promoter. Furthermore, we show that MglA–SspA must be bound to ppGpp to mediate high-affinity interactions with PigR. Thus, these studies unveil a novel pathway different from those described previously for regulation of transcription by ppGpp. The data also indicate that F. tularensis pathogenesis is controlled by a highly interconnected molecular circuitry in which the virulence machinery directly senses infection via a small molecule stress signal. |
format | Online Article Text |
id | pubmed-5630020 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56300202017-10-13 Dissection of the molecular circuitry controlling virulence in Francisella tularensis Cuthbert, Bonnie J. Ross, Wilma Rohlfing, Amy E. Dove, Simon L. Gourse, Richard L. Brennan, Richard G. Schumacher, Maria A. Genes Dev Research Paper Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators—the heteromeric macrophage growth locus protein A (MglA)–stringent starvation protein A (SspA) complex and the DNA-binding protein pathogenicity island gene regulator (PigR)—activates FPI transcription and thus is essential for virulence. Intriguingly, the second messenger, guanosine–tetraphosphate (ppGpp), which is produced during infection, is also involved in coordinating Francisella virulence; however, its role has been unclear. Here we identify MglA–SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA–SspA. We demonstrate that MglA–SspA, which binds RNA polymerase (RNAP), also interacts with the C-terminal domain of PigR, thus anchoring the (MglA–SspA)–RNAP complex to the FPI promoter. Furthermore, we show that MglA–SspA must be bound to ppGpp to mediate high-affinity interactions with PigR. Thus, these studies unveil a novel pathway different from those described previously for regulation of transcription by ppGpp. The data also indicate that F. tularensis pathogenesis is controlled by a highly interconnected molecular circuitry in which the virulence machinery directly senses infection via a small molecule stress signal. Cold Spring Harbor Laboratory Press 2017-08-01 /pmc/articles/PMC5630020/ /pubmed/28864445 http://dx.doi.org/10.1101/gad.303701.117 Text en © 2017 Cuthbert et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Paper Cuthbert, Bonnie J. Ross, Wilma Rohlfing, Amy E. Dove, Simon L. Gourse, Richard L. Brennan, Richard G. Schumacher, Maria A. Dissection of the molecular circuitry controlling virulence in Francisella tularensis |
title | Dissection of the molecular circuitry controlling virulence in Francisella tularensis |
title_full | Dissection of the molecular circuitry controlling virulence in Francisella tularensis |
title_fullStr | Dissection of the molecular circuitry controlling virulence in Francisella tularensis |
title_full_unstemmed | Dissection of the molecular circuitry controlling virulence in Francisella tularensis |
title_short | Dissection of the molecular circuitry controlling virulence in Francisella tularensis |
title_sort | dissection of the molecular circuitry controlling virulence in francisella tularensis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630020/ https://www.ncbi.nlm.nih.gov/pubmed/28864445 http://dx.doi.org/10.1101/gad.303701.117 |
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