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Sponsored by: Honors Program
Seminars: Why so Many Ways to Die? The Non-canonical Inflammasome Pathway
Start Date/Time: 5/22/2017 4:00 PM
End Date/Time: 5/22/2017 5:00 PM
Description: 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.
Contact: Josephine Markiewicz
Phone: 263-3815
Email: Josephine.Markiewicz@nyumc.org
Speaker: Vishva M. Dixit, M.D.
Speaker Institution: Genentech, Inc.
Speaker Institution Location: South San Francisco, CA
Speaker Position: Vice President-Research
Seminar Host: Dan Littman
Refreshments: No
Fee Required: No
Fee Amount:

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