Phosphatidylinositol 4,5-Bisphosphate-Dependent Oligomerization of the Pseudomonas aeruginosa Cytotoxin ExoU

Angelica Zhang, Jeffrey L Veesenmeyer, Alan R Hauser
Infection and Immunity 2018, 86 (1)
The Pseudomonas aeruginosa type III secretion system delivers effector proteins directly into target cells, allowing the bacterium to modulate host cell functions. ExoU is the most cytotoxic of the known effector proteins and has been associated with more severe infections in humans. ExoU is a patatin-like A2 phospholipase requiring the cellular host factors phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 ] and ubiquitin for its activation in vitro We demonstrated that PI(4,5)P2 also induces the oligomerization of ExoU and that this PI(4,5)P2 -mediated oligomerization does not require ubiquitin. Single amino acid substitutions in the C-terminal membrane localization domain of ExoU reduced both its activity and its ability to form higher-order complexes in transfected cells and in vitro Combining inactive truncated ExoU proteins partially restored phospholipase activity and cytotoxicity, indicating that ExoU oligomerization may have functional significance. Our results indicate that PI(4,5)P2 induces the oligomerization of ExoU, which may be a mechanism by which this coactivator enhances the phospholipase activity of ExoU.

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