Structural Basis for Virulence Activation of Francisella tularensis.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Travis, BA; Ramsey, KM; Prezioso, SM; Tallo, T; Wandzilak, JM; Hsu, A; Borgnia, M; Bartesaghi, A; Dove, SL; Brennan, RG; Schumacher, MA

Published Date

  • January 7, 2021

Published In

Volume / Issue

  • 81 / 1

Start / End Page

  • 139 - 152.e10

PubMed ID

  • 33217319

Pubmed Central ID

  • PMC7959165

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2020.10.035

Language

  • eng

Conference Location

  • United States