On 28th November OxTalks will move to the new Halo platform and will become 'Oxford Events' (full details are available on the Staff Gateway).
There will be an OxTalks freeze beginning on Friday 14th November. This means you will need to publish any of your known events to OxTalks by then as there will be no facility to publish or edit events in that fortnight. During the freeze, all events will be migrated to the new Oxford Events site. It will still be possible to view events on OxTalks during this time.
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Intracellular lipopolysaccharide (LPS) from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11 causing pyroptotic cell death, IL-1 processing, and lethal septic shock. How caspase-11 drives these downstream signaling events is largely unknown. Here we show that Gasdermin-D (Gsdmd) is essential for caspase-11-dependent pyroptosis and IL-1 maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice linked Gsdmd to the intracellular LPS response. Macrophages from Gsdmd–/– mice generated by gene targeting also exhibited defective pyroptosis and IL-1 secretion induced by cytoplasmic LPS or Gram-negative bacteria. In addition, Gsdmd–/– mice were protected from a lethal dose of LPS. Mechanistically, caspase-11 cleaved Gsdmd and the N-terminal Gsdmd fragment promoted both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify Gsdmd as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacterial infection. At the meeting I’ll give an update on the discovery of an additional mediator of pyroptosis: IRF2, a transcriptional factor that drives the expression of Gsdmd. In it’s absence cells and mice are resistant to LPS challenge. In sum we have defined a new pathway for LPS responsiveness that may have therapeutic potential.