The Non-Canonical Inflammasome Pathway | HBKU
Hamad Bin Khalifa University

Events

The Non-Canonical Inflammasome Pathway

16Sep2021
  • 05:00 PM - 06:00 PM
  • College of Health and Life Sciences
  • Webex Events
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-1b processing, and lethal septic shock. How caspase-11 drives these downstream signaling events is largely unknown.

Gasdermin-D (Gsdmd) is essential for caspase-11-dependent pyroptosis and IL-1b 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-1b 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.

This webinar will provide an update on the discovery of NINJ1, a mediator of plasma cell rupture, the final cataclysmic event in lytic cell death. NINJ1 is a cell surface protein with two transmembrane regions. Its discovery overturns long-held dogma that cell death-related plasma membrane rupture is a passive event.

Speaker:

  • Dr. Vishva M. Dixit Vice President of Discovery Research, Genentech (Subsidiary of Roche)

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