The non-canonical Inflammasome Pathway
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.
Date: 5 September 2019, 16:00 (Thursday, 19th week, Trinity 2019)
Venue: Sherrington Building, off Parks Road OX1 3PT
Venue Details: Large Lecture Theatre
Speaker: Dr Vishva Dixit (Vice President –Research, Genentech)
Organising department: Department of Physiology, Anatomy and Genetics (DPAG)
Organisers: Katherine McNeil (University of Oxford, Department of Physiology Anatomy and Genetics), Sarah Noujaim (University of Oxford, Department of Physiology Anatomy and Genetics), Professor Dame Carol Robinson (University of Oxford)
Organiser contact email address:
Host: Professor Dame Carol Robinson (University of Oxford)
Part of: DPAG Guest Speakers
Booking required?: Not required
Audience: Members of the University only
Editor: Talitha Smith