PMID:18234841
| Citation |
Wiles, TJ, Dhakal, BK, Eto, DS and Mulvey, MA (2008) Inactivation of host Akt/protein kinase B signaling by bacterial pore-forming toxins. Mol. Biol. Cell 19:1427-38 |
|---|---|
| Abstract |
Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs), and they 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. |
| Links |
PubMed PMC2291440 Online version:10.1091/mbc.E07-07-0638 |
| Keywords |
Bacterial Toxins/toxicity; Base Sequence; Cell Line; DNA, Bacterial/genetics; Epithelial Cells/drug effects; Epithelial Cells/enzymology; Escherichia coli/pathogenicity; Escherichia coli Proteins/toxicity; Hemolysin Proteins/toxicity; Humans; Pore Forming Cytotoxic Proteins/toxicity; Proto-Oncogene Proteins c-akt/antagonists & inhibitors; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism; RNA, Small Interfering/genetics; Recombinant Proteins/antagonists & inhibitors; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Signal Transduction/drug effects; Urinary Bladder/cytology; Urinary Bladder/enzymology; Urinary Tract Infections/etiology |
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