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MBC in Press, published online ahead of print January 30, 2008
Mol. Biol. Cell 10.1091/mbc.E07-07-0638

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Submitted on July 5, 2007
Revised on November 1, 2007
Accepted on January 23, 2008

Inactivation of Host AKT/PKB Signaling by Bacterial Pore-Forming Toxins

Travis J. Wiles, Bijaya K. Dhakal, Danelle S. Eto, and Matthew A. Mulvey

Division of Cell Biology and Immunology, Pathology Department, University of Utah, Salt Lake City, UT 84112-0565

Monitoring Editor: John York

Uropathogenic E. coli (UPEC) are the major cause of urinary tract infections (UTIs) and have the capacity to induce the death and exfoliation of target uroepithelial cells. This process can be facilitated by the pore forming toxin {alpha}-hemolysin (HlyA), which is expressed and secreted by many UPEC isolates. Here we demonstrate that HlyA can potently inhibit activation of Akt (protein kinase B), a key regulator of host cell survival, inflammatory responses, proliferation and metabolism. HlyA ablates Akt activation via an extracellular calcium-dependent, potassium-independent process requiring HlyA insertion into the host plasma membrane and subsequent pore formation. Inhibitor studies indicate that Akt inactivation by HlyA involves aberrant stimulation of host protein phosphatases. We found that two other bacterial pore-forming toxins (aerolysin from Aeromonas species and {alpha}-toxin from Staphylococcus aureus) can also markedly attenuate Akt activation in a dose-dependent manner. These data suggest a novel mechanism by which sublytic concentrations of HlyA and other pore-forming toxins can modulate host cell survival and inflammatory pathways during the course of a bacterial infection.

Address correspondence to: Matthew A. Mulvey (mulvey{at}path.utah.edu)






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