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Opposing effects of histidine phosphorylation regulate the AtxA virulence transcription factor in Bacillus anthracis

Billyana Tsvetanova1, Adam C Wilson, Cristina Bongiorni

  • 1The Scripps Research Institute, Department of Molecular and Experimental Medicine, Division of Cellular Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Molecular Microbiology
|February 17, 2007
PubMed

Insights

Bacillus anthracis virulence is controlled by the AtxA transcription factor. Phosphorylation of specific AtxA domains regulates toxin and capsule gene expression, linking bacterial virulence to carbohydrate metabolism.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • The expression of Bacillus anthracis virulence factors, including toxin and capsule genes, is regulated by the AtxA transcription factor.
  • The precise mechanism by which AtxA controls gene transcription remains largely unelucidated.

Purpose of the Study:

  • To investigate the regulatory mechanism of the AtxA transcription factor in Bacillus anthracis.
  • To elucidate the role of phosphorylation in AtxA's transcriptional activity and its link to virulence factor production.

Main Methods:

  • Bioinformatic analysis to identify potential regulatory domains within AtxA.
  • Site-directed mutagenesis to mimic phosphorylated (H to D) and unphosphorylated (H to A) states of conserved histidine residues.
  • In vivo radioactive labeling experiments to detect phosphorylation of AtxA.
  • Genetic manipulation involving deletion of PTS genes (ptsHI) and growth in the presence of glucose.

Main Results:

  • Bioinformatic analysis identified two phosphoregulation domains (PRDs) in AtxA, typically regulated by histidine phosphorylation/dephosphorylation.
  • Phosphorylation of H199 in PRD1 is essential for AtxA activation, while phosphorylation of H379 in PRD2 inhibits toxin gene transcription.
  • In vivo labeling confirmed that H199 and H379 are sites of regulated phosphorylation.
  • Deletion of PTS genes (ptsHI) enhanced AtxA activity, whereas growth with glucose reduced it.

Conclusions:

  • AtxA activity and subsequent virulence factor production in Bacillus anthracis are directly linked to carbohydrate metabolism via the phosphotransferase system (PTS).
  • This study provides the first mechanistic explanation for AtxA's transcriptional regulation, involving phosphorylation-dependent activation and inhibition.
  • The findings establish a novel connection between bacterial metabolism and virulence gene expression in B. anthracis.

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