title: Spontaneous formation of IpaB ion channels in host cell membranes reveals how Shigella induces pyroptosis in macrophages.
abstract: The Gram-negative bacterium Shigella flexneri invades the colonic epithelium and causes bacillary dysentery. S. flexneri requires the virulence factor invasion plasmid antigen B (IpaB) to invade host cells, escape from the phagosome and induce macrophage cell death. The mechanism by which IpaB functions remains unclear. Here, we show that purified IpaB spontaneously oligomerizes and inserts into the plasma membrane of target cells forming cation selective ion channels. After internalization, IpaB channels permit potassium influx within endolysosomal compartments inducing vacuolar destabilization. Endolysosomal leakage is followed by an ICE protease-activating factor-dependent activation of Caspase-1 in macrophages and cell death. Our results provide a mechanism for how the effector protein IpaB with its ion channel activity causes phagosomal destabilization and induces macrophage death. These data may explain how S. flexneri uses secreted IpaB to escape phagosome and kill the host cells during infection and, may be extended to homologs from other medically important enteropathogenic bacteria.
authors.affiliation: Department of Cellular Microbiology, Max-Planck-Institute for Infection Biology, Charitéplatz 1, D-10117 Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Senerovic
authors.forename: S P
authors.initials: SP
authors.lastname: Tsunoda
authors.forename: C
authors.initials: C
authors.lastname: Goosmann
authors.forename: V
authors.initials: V
authors.lastname: Brinkmann
authors.forename: A
authors.initials: A
authors.lastname: Zychlinsky
authors.forename: F
authors.initials: F
authors.lastname: Meissner
authors.forename: M
authors.initials: M
authors.lastname: Kolbe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D020170:Caspase 1 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology / Q000382:microbiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D011188:Potassium / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D012763:Shigella flexneri / Q000378:metabolism*; D014982:Xenopus laevis / Q000254:growth & development
chemical_list: D001426:Bacterial Proteins; D007473:Ion Channels; D011994:Recombinant Proteins; C087447:ipaB protein, Shigella; D020170:Caspase 1; D011188:Potassium