Phosphatidylinositol 4,5-bisphosphate is a novel coactivator of the pseudomonas aeruginosa cytotoxin exoU

Gregory H. Tyson, Alan R. Hauser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

ExoU is a potent phospholipase A2 effector protein secreted by the type III secretion system of Pseudomonas aeruginosa. By cleaving plasma membrane phospholipids, it causes rapid lysis of eukaryotic cells. However, ExoU does not exhibit activity on its own but instead requires eukaryotic cell cofactors for activation. Ubiquitin and ubiquitinated proteins have been shown to activate ExoU, but previous work suggested that other cofactors are also involved. In this study, we demonstrate that phosphatidyl-inositol 4,5-bisphosphate [PI(4,5)P2] is another important coactivator of ExoU. PI(4,5)P2 works synergistically with ubiquitin to greatly enhance the phospholipase A2 activity of ExoU. Distinct residues of ExoU were critical for activation by PI(4,5)P2 and by ubiquitin, indicating that these factors activate ExoU by discrete mechanisms. In support of the biological relevance of PI(4,5)P2 coactivation, a yeast mutant with reduced PI(4,5)P2 levels was less susceptible to the cytotoxic activity of ExoU. Together, these findings further elaborate the molecular mechanism of ExoU.

Original languageEnglish (US)
Pages (from-to)2873-2881
Number of pages9
JournalInfection and immunity
Volume81
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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