A pH-sensitive switch activates virulence in Salmonella

  1. Dasvit Shetty
  2. Linda J Kenney  Is a corresponding author
  1. National University of Singapore, Singapore
  2. The University of Texas Medical Branch at Galveston, United States

Abstract

The transcriptional regulator SsrB acts as a switch between virulent and biofilm lifestyles of non-typhoidal Salmonella enterica serovar Typhimurium. During infection, phosphorylated SsrB activates genes on Salmonella Pathogenicity Island-2 (SPI-2) essential for survival and replication within the macrophage. Low pH inside the vacuole is a key inducer of expression and SsrB activation. Previous studies demonstrated an increase in SsrB protein levels and DNA-binding affinity at low pH; the molecular basis was unknown (Liew et al., 2019). This study elucidates its underlying mechanism and in vivo significance. Employing single-molecule and transcriptional assays, we report that the SsrB DNA binding domain alone (SsrBc) is insufficient to induce acid pH-sensitivity. Instead, His12, a conserved residue in the receiver domain, confers pH sensitivity to SsrB allosterically. Acid-dependent DNA binding was highly cooperative, suggesting a new configuration of SsrB oligomers at SPI-2-dependent promoters. His12 also plays a role in SsrB phosphorylation; substituting His12 reduced phosphorylation at neutral pH and abolished pH-dependent differences. Failure to flip the switch in SsrB renders Salmonella avirulent and represents a potential means of controlling virulence.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-4, and figure supplements for Figures 2 and 3.

Article and author information

Author details

  1. Dasvit Shetty

    Mechanobiology Institute, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8778-3615
  2. Linda J Kenney

    2Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, United States
    For correspondence
    likenney@utmb.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8658-0717

Funding

Mechanobiology Institute, Singapore (Regional centre of excellence)

  • Dasvit Shetty
  • Linda J Kenney

University of Texas Medical Branch

  • Linda J Kenney

Cancer Prevention and Research Institute of Texas (RP200650)

  • Linda J Kenney

Texas STAR

  • Linda J Kenney

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Detlef Weigel, Max Planck Institute for Biology Tübingen, Germany

Version history

  1. Preprint posted: December 16, 2022 (view preprint)
  2. Received: December 20, 2022
  3. Accepted: September 13, 2023
  4. Accepted Manuscript published: September 14, 2023 (version 1)
  5. Version of Record published: September 25, 2023 (version 2)

Copyright

© 2023, Shetty & Kenney

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Dasvit Shetty
  2. Linda J Kenney
(2023)
A pH-sensitive switch activates virulence in Salmonella
eLife 12:e85690.
https://doi.org/10.7554/eLife.85690

Share this article

https://doi.org/10.7554/eLife.85690

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