title: Inactivation of host Akt/protein kinase B signaling by bacterial pore-forming toxins.
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.
authors.affiliation: Division of Cell Biology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112-0565, USA.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Wiles
authors.forename: Bijaya K
authors.initials: BK
authors.lastname: Dhakal
authors.forename: Danelle S
authors.initials: DS
authors.lastname: Eto
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mulvey
mesh_terms: D001427:Bacterial Toxins / Q000633:toxicity*; D001483:Base Sequence; D002460:Cell Line; D004269:DNA, Bacterial / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D004926:Escherichia coli / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000633:toxicity*; D006460:Hemolysin Proteins / Q000633:toxicity*; D006801:Humans; D052899:Pore Forming Cytotoxic Proteins / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D001743:Urinary Bladder / Q000166:cytology / Q000201:enzymology; D014552:Urinary Tract Infections / Q000209:etiology
chemical_list: D001427:Bacterial Toxins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D052899:Pore Forming Cytotoxic Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051057:Proto-Oncogene Proteins c-akt