Structural Basis for Virulence Activation of Francisella tularensis

Authors

Brady A. Travis, Duke University School of Medicine
Kathryn M. Ramsey, University of Rhode Island
Samantha M. Prezioso, Harvard Medical School
Thomas Tallo, Harvard Medical School
Jamie M. Wandzilak, University of Rhode Island
Allen Hsu, National Institute of Environmental Health Sciences (NIEHS)
Mario Borgnia, National Institute of Environmental Health Sciences (NIEHS)
Alberto Bartesaghi, Duke University School of Medicine
Simon L. Dove, Harvard Medical School
Richard G. Brennan, Duke University School of Medicine
Maria A. Schumacher, Duke University School of Medicine

Document Type

Article

Date of Original Version

1-7-2021

Abstract

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.

Publication Title, e.g., Journal

Molecular Cell

Volume

81

Issue

1

Citation/Publisher Attribution

Travis, Brady A., Kathryn M. Ramsey, Samantha M. Prezioso, Thomas Tallo, Jamie M. Wandzilak, Allen Hsu, Mario Borgnia, Alberto Bartesaghi, Simon L. Dove, Richard G. Brennan, and Maria A. Schumacher. "Structural Basis for Virulence Activation of Francisella tularensis." Molecular Cell 81, 1 (2021): 139-152.e10. doi: 10.1016/j.molcel.2020.10.035.

Comment

Kathryn M. Ramsey is affiliated with the Department of Cell and Molecular Biology and the Department of Biomedical and Pharmaceutical Sciences.