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Structural Basis for Virulence Activation of Francisella tularensis.
Travis, Brady A; Ramsey, Kathryn M; Prezioso, Samantha M; Tallo, Thomas; Wandzilak, Jamie M; Hsu, Allen; Borgnia, Mario; Bartesaghi, Alberto; Dove, Simon L; Brennan, Richard G; Schumacher, Maria A.
Affiliation
  • Travis BA; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
  • Ramsey KM; Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cell and Molecular Biology and Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
  • Prezioso SM; Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Tallo T; Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Wandzilak JM; Department of Cell and Molecular Biology and Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
  • Hsu A; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
  • Borgnia M; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
  • Bartesaghi A; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA; Department of Computer Science, Duke University, Durham, NC 27708, USA.
  • Dove SL; Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: simon.dove@childrens.harvard.edu.
  • Brennan RG; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: richard.brennan@duke.edu.
  • Schumacher MA; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: maria.schumacher@duke.edu.
Mol Cell ; 81(1): 139-152.e10, 2021 01 07.
Article in En | MEDLINE | ID: mdl-33217319
The bacterium Francisella tularensis (Ft) is one of the most infectious agents known. Ft virulence is controlled by a unique combination of transcription regulators: the MglA-SspA heterodimer, PigR, and the stress signal, ppGpp. MglA-SspA assembles with the σ70-associated RNAP holoenzyme (RNAPσ70), forming a virulence-specialized polymerase. These factors activate Francisella pathogenicity island (FPI) gene expression, which is required for virulence, but the mechanism is unknown. Here we report FtRNAPσ70-promoter-DNA, FtRNAPσ70-(MglA-SspA)-promoter DNA, and FtRNAPσ70-(MglA-SspA)-ppGpp-PigR-promoter DNA cryo-EM structures. Structural and genetic analyses show MglA-SspA facilitates σ70 binding to DNA to regulate virulence and virulence-enhancing genes. Our Escherichia coli RNAPσ70-homodimeric EcSspA structure suggests this is a general SspA-transcription regulation mechanism. Strikingly, our FtRNAPσ70-(MglA-SspA)-ppGpp-PigR-DNA structure reveals ppGpp binding to MglA-SspA tethers PigR to promoters. PigR in turn recruits FtRNAP αCTDs to DNA UP elements. Thus, these studies unveil a unique mechanism for Ft pathogenesis involving a virulence-specialized RNAP that employs two (MglA-SspA)-based strategies to activate virulence genes.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sigma Factor / DNA-Directed RNA Polymerases / Promoter Regions, Genetic / Virulence Factors / Francisella tularensis Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sigma Factor / DNA-Directed RNA Polymerases / Promoter Regions, Genetic / Virulence Factors / Francisella tularensis Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2021 Type: Article Affiliation country: United States