Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 16, Issue 5, Pages 2577-2585Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E04-08-0717
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Funding
- NHLBI NIH HHS [HL-55980, R01 HL055980] Funding Source: Medline
- NIAID NIH HHS [AI-42806, R01 AI042806] Funding Source: Medline
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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)P-3] to polarized MDCK cells was sufficient to increase PAK internalization. PtdIns(3,4,5)P-3 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.
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