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.

doi:10.1101/gad.303701.117

Title: Dissection of the molecular circuitry controlling virulence in Francisella tularensis

Journal Article · 31 August 2017 · Genes & Development

DOI: https://doi.org/10.1101/gad.303701.117 · OSTI ID:1625616

Cuthbert, Bonnie J. ^[1]; Ross, Wilma ^[2]; Rohlfing, Amy E. ^[3]; Dove, Simon L. ^[3]; Gourse, Richard L. ^[2]; Brennan, Richard G. ^[4]; Schumacher, Maria A. ^[4]

Duke Univ., School of Medicine, Durham, NC (United States). Dept. of Biochemistry; DOE/OSTI
Univ. of Wisconsin, Madison, WI (United States). Dept. of Bacteriology
Harvard Medical School, Boston, MA (United States). Division of Infectious Diseases, Boston Children’s Hospital
Duke Univ., School of Medicine, Durham, NC (United States). Dept. of Biochemistry

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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Research Organization:: Univ. of California, Oakland, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Howard Hughes Medical Institute

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625616

Journal Information:: Genes & Development, Journal Name: Genes & Development Journal Issue: 15 Vol. 31; ISSN 0890-9369

Publisher:: Cold Springs Harbor Laboratory PressCopyright Statement

Country of Publication:: United States

Language:: English

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Two-Component Systems in Francisella Species van Hoek, Monique L.; Hoang, Ky V.; Gunn, John S. Frontiers in Cellular and Infection Microbiology, Vol. 9 https://doi.org/10.3389/fcimb.2019.00198	journal	June 2019
Critical Role of a Sheath Phosphorylation Site On the Assembly and Function of an Atypical Type VI Secretion System Ziveri, Jason; Chhuon, Cerina; Jamet, Anne Molecular & Cellular Proteomics, Vol. 18, Issue 12 https://doi.org/10.1074/mcp.ra119.001532	journal	October 2019
HU protein is involved in intracellular growth and full virulence of Francisella tularensis Stojkova, Pavla; Spidlova, Petra; Lenco, Juraj Virulence, Vol. 9, Issue 1 https://doi.org/10.1080/21505594.2018.1441588	journal	April 2018
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HU protein is involved in intracellular growth and full virulence of Francisella tularensis Stojkova, Pavla; Spidlova, Petra; Lenco, Juraj Taylor & Francis https://doi.org/10.6084/m9.figshare.7491923	text	January 2018
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59 BASIC BIOLOGICAL SCIENCES
Cell Biology
Developmental Biology
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Francisella tularensis
PigR
MglA
SspA
Bioterrorism
ppGpp
Virulence

Title: Dissection of the molecular circuitry controlling virulence in Francisella tularensis

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