Why So Many Ways To Die?
The Maclyn McCarty Memorial Lecture
Event Details
- Type
- Friday Lecture Series
- Speaker(s)
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Vishva Dixit, M.D., vice president and senior fellow, physiological chemistry, research biology, Genentech
- Speaker bio(s)
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The two key takeaway messages from Dr. Dixit's talk will be:
• Leaderless cytokines (IL-1a, IL-1b, IL-18, IL-33) are released via GSDMD pores.
• Cell lysis following cell death is not a passive event but one greatly accelerated by NINJ1.
Intracellular lipopolysaccharide (LPS) from Gram-negative bacteria activates caspase-11, causing inflammatory cell death (pyroptosis), IL-1β processing, and lethal septic shock. How caspase-11 drives these downstream signaling events is largely unknown. In 2015, the Dixit Lab demonstrated that Gasdermin-D (Gsdmd) is essential for caspase-11-dependent pyroptosis and IL-1β release. Macrophages from Gsdmd–/– mice generated through gene targeting exhibited defective pyroptosis and IL-1β release in response to cytoplasmic LPS or Gram-negative bacteria. Mechanistically, caspase-11 cleaves Gsdmd, and the newly generated N-terminal fragment assembles into an oligomeric plasma membrane pore, allowing the release of IL-1β and other leaderless cytokines. At this talk, Dr. Dixit will also provide an update on the unexpected discovery of a mediator of cell lysis: NINJ1, a transmembrane protein that drives the formation of megapores in dying cells, thereby accelerating lysis.
Born in Kenya, Dr. Vishva Dixit attended medical school at the University of Nairobi. Following clinical work at the Kenyatta National Hospital, he trained in Pathology at Washington University in St. Louis. In 1986, Dr. Dixit joined the Department of Pathology at the University of Michigan and rose to Professor. He left in 1997 to join Genentech, where he is currently Vice President of Research. Dr. Dixit is a member of the National Academy of Sciences and and a Foreign Member of the Royal Society. In 2022, he received the Heineken Prize for Medicine and the Vilcek Prize in Biomedical Science. Dr. Dixit serves on the HHMI Medical Advisory Board and the Bill and Melinda Gates Foundation's External Scientific Advisory Group.
- Open to
- Tri-Institutional