The Abi-domain protein Abx1 interacts with the CovS histidine kinase to control virulence gene expression in group B Streptococcus

PLoS Pathog. 2013 Feb;9(2):e1003179. doi: 10.1371/journal.ppat.1003179. Epub 2013 Feb 21.


Group B Streptococcus (GBS), a common commensal of the female genital tract, is the leading cause of invasive infections in neonates. Expression of major GBS virulence factors, such as the hemolysin operon cyl, is regulated directly at the transcriptional level by the CovSR two-component system. Using a random genetic approach, we identified a multi-spanning transmembrane protein, Abx1, essential for the production of the GBS hemolysin. Despite its similarity to eukaryotic CaaX proteases, the Abx1 function is not involved in a post-translational modification of the GBS hemolysin. Instead, we demonstrate that Abx1 regulates transcription of several virulence genes, including those comprising the hemolysin operon, by a CovSR-dependent mechanism. By combining genetic analyses, transcriptome profiling, and site-directed mutagenesis, we showed that Abx1 is a regulator of the histidine kinase CovS. Overexpression of Abx1 is sufficient to activate virulence gene expression through CovS, overcoming the need for an additional signal. Conversely, the absence of Abx1 has the opposite effect on virulence gene expression consistent with CovS locked in a kinase-competent state. Using a bacterial two-hybrid system, direct interaction between Abx1 and CovS was mapped specifically to CovS domains involved in signal processing. We demonstrate that the CovSR two-component system is the core of a signaling pathway integrating the regulation of CovS by Abx1 in addition to the regulation of CovR by the serine/threonine kinase Stk1. In conclusion, our study reports a regulatory function for Abx1, a member of a large protein family with a characteristic Abi-domain, which forms a signaling complex with the histidine kinase CovS in GBS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Epistasis, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial*
  • Hemolysis
  • Histidine Kinase
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Pigments, Biological / metabolism
  • Protein Interaction Mapping
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Sequence Alignment
  • Signal Transduction*
  • Streptococcal Infections / microbiology*
  • Streptococcus agalactiae / genetics*
  • Streptococcus agalactiae / metabolism
  • Streptococcus agalactiae / pathogenicity
  • Virulence / genetics
  • Virulence Factors / genetics


  • Bacterial Proteins
  • Pigments, Biological
  • Virulence Factors
  • Protein Kinases
  • Stk1 protein, Streptococcus agalactiae
  • Protein Serine-Threonine Kinases
  • Histidine Kinase
  • Phosphoprotein Phosphatases