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Vol. 16, Issue 5, 2577-2585, May 2005

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The Phosphoinositol-3-Kinase–Protein Kinase B/Akt Pathway Is Critical for Pseudomonas aeruginosa Strain PAK Internalization

A. Kierbel ^* , A. Gassama-Diagne   ^||, K. Mostov   ^||, and J. N. Engel ^*  ||

^* Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143; Department of Biochemistry, University of California, San Francisco, San Francisco, CA 94143; and ^|| Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143

Submitted August 19, 2004; Revised February 23, 2005; Accepted February 28, 2005
Monitoring Editor: Jennifer Lippincott-Schwartz

Several Pseudomonas aeruginosa strains are internalized by epithelial cells in vitro and in vivo, but the host pathways usurped by the bacteria to enter nonphagocytic cells are not clearly understood. Here, we report that internalization of strain PAK into epithelial cells triggers and requires activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B/Akt (Akt). Incubation of Madin-Darby canine kidney (MDCK) or HeLa cells with the PI3K inhibitors LY294002 (LY) or wortmannin abrogated PAK uptake. Addition of the PI3K product phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P₃] to polarized MDCK cells was sufficient to increase PAK internalization. PtdIns(3,4,5)P₃ accumulated at the site of bacterial binding in an LY-dependent manner. Akt phosphorylation correlated with PAK invasion. The specific Akt phosphorylation inhibitor SH-5 inhibited PAK uptake; internalization also was inhibited by small interfering RNA-mediated depletion of Akt phosphorylation. Expression of constitutively active Akt was sufficient to restore invasion when PI3K signaling was inhibited. Together, these results demonstrate that the PI3K signaling pathway is necessary and sufficient for the P. aeruginosa entry and provide the first example of a bacterium that requires Akt for uptake into epithelial cells.

Address correspondence to: J. N. Engel (Jengel{at}medicine.ucsf.edu).

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