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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...

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Autores principales: Cuthbert, Bonnie J., Ross, Wilma, Rohlfing, Amy E., Dove, Simon L., Gourse, Richard L., Brennan, Richard G., Schumacher, Maria A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
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.
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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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