Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence

Mol Microbiol. 2003 Jun;48(6):1565-78. doi: 10.1046/j.1365-2958.2003.03524.x.


Clp proteolytic complexes are essential for virulence and for survival under stress conditions in several pathogenic bacteria. Recently, a study using signature-tagged mutagenesis identified the ClpX ATPase as also being required for virulence in Staphylococcus aureus. Presently, we have constructed deletion mutants removing either ClpX or the proteolytic subunit, ClpP, in S. aureus 8325-4 in order to examine a putative link between stress tolerance and virulence. When exposed to stress, we found that, although clpP mutant cells were sensitive to conditions generating misfolded proteins, the absence of ClpX improved survival. In the presence of oxidative stress or at low temperature, both ClpP and ClpX were important for growth. Virulence was examined in a murine skin abscess model and was found to be severely attenuated for both mutants. S. aureus pathogenicity is largely dependent on a set of extracellular and cell wall-associated proteins. In the mutant cells, the amount of alpha-haemolysin (hla) and several other extracellular proteins was greatly decreased, and analysis of hla expression revealed that the reduction occurred at the transcriptional level. Essential for transcriptional regulation of hla is the quorum-sensing agr locus. Interestingly, the absence of ClpX or ClpP reduced both transcription of the agr effector molecule, RNA III, and the activity of the autoinducing peptide (AIP). In addition, ClpX was required independently of ClpP for transcription of spa encoding Protein A. Thus, our results indicate that ClpX and ClpP contribute to virulence by controlling the activity of major virulence factors rather than by promoting stress tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Abscess / microbiology*
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Endopeptidase Clp
  • Escherichia coli Proteins
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Bacterial
  • Heat-Shock Response
  • Hemolysin Proteins / genetics
  • Hemolysin Proteins / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Chaperones
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Skin Diseases, Bacterial / microbiology*
  • Skin Diseases, Bacterial / physiopathology
  • Staphylococcal Infections / microbiology
  • Staphylococcal Infections / physiopathology
  • Staphylococcus aureus / pathogenicity*
  • Staphylococcus aureus / physiology*
  • Virulence


  • Escherichia coli Proteins
  • Hemolysin Proteins
  • Molecular Chaperones
  • Serine Endopeptidases
  • Endopeptidase Clp
  • Adenosine Triphosphatases
  • ClpX protein, E coli
  • ATPases Associated with Diverse Cellular Activities