Gasdermin-mediated pyroptosis: from antibacterial to antitumor immunity

Gasdermina are pore-forming proteins conserved from humans to bacteria and execute pyroptosis to stimulate immune responses. GSDMD is cleaved/activated by canonical inflammasome-stimulated caspase-1 and cytosolic LPS-ligated caspase-4/5/11. I will present the finding that LPS-activated caspase-4/5, but not mouse caspase-11, processes IL-18 in vitro and during bacterial infections, which mainly operates in epithelial cells. LPS-activated caspase-4/11, when occurring in brain endothelial cells, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Lastly, I will discuss the role of pyroptosis in stimulating antitumor immunity. Specifically, cytotoxic lymphocytes kill GSDMB-positive cells through pyroptosis, mediated by granzyme A cleavage of GSDMB. IFN-g upregulates GSDMB and promotes pyroptosis of cancer cells including that by CAR-T/TCR-T cells.

 

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From 22 Apr 2024 10:00
Until 22 Apr 2024 11:30
Location FSVM I building, seminar room

Speaker Feng Shao
Affiliation Investigator and Deputy Director, National Institute of Biological Sciences, Bejing, China
Host Peter Vandenabeele

Stream View stream
Stream ID 886 3354 1485
Stream Password 103382

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About the speaker

Dr. Feng Shao is an investigator and deputy director at National Institute of Biological Sciences (NIBS), Beijing, China. He was a chemistry undergraduate of Peking University (1991-1996) and obtained his PhD with Dr. Jack E. Dixon from University of Michigan in 2003. Prior to returning to China in 2005 to assume an assistant investigator at NIBS, he was a Damon Runyon Postdoc Research Fellow at Harvard Medical School. Dr. Shao was promoted to become an associate investigator in 2009 and a full investigator in 2012 at NIBS. He has also been appointed as an Endowed Chair Professor of Tsinghua University since 2020.

Dr. Shao’s research lies at the interface between bacterial pathogen and host inflammation. He identified most of the known cytosolic receptors for bacterial molecules, including caspase-11/4/5 for LPS and ALPK1 for ADP-heptose in LPS biosynthesis. He also identified gasdermin-D (GSDMD) whose cleavage by caspase-1/4/5/11 determines pyroptosis, critical for septic shock and other inflammatory diseases. His research establishes the gasdermin family of pore-forming proteins, re-defining pyroptosis as gasdermin-mediated programmed necrosis. Among the family, GSDME is activated by caspase-3, which occurs mostly in noncancer cells and contributes to toxicity of chemotherapy drugs. His most recent work demonstrates that pyroptosis is a critical mechanism underlying lymphocyte cytotoxicity and gasdermin activation can stimulate potent antitumor immunity.

Dr. Shao’s work has been recognized by numerous awards including the Future Science Prize, the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology, HHMI International Early Career Award and the Protein Society Irving Sigal Young Investigator Award. He is an elected member of the Chinese Academy of Sciences and the German National Academy of Sciences Leopoldina, an associate member of EMBO, and a fellow of American Academy of Microbiology and Chinese Academy of Medical Sciences.