Inflammasome - activated gasdermin D causes pyroptosis by forming membrane pores

Inflammasome - activated gasdermin D causes pyroptosis by forming membrane pores

2016 July 07; 535(7610): 153–158. doi:10.1038/nature18629 | Xing Liu, Zhibin Zhang, Jianbin Ruan, Youdong Pan, Venkat Giri Magupalli, Hao Wu, and Judy Lieberman
The study investigates the mechanism by which gasdermin D (GSDMD) triggers pyroptosis, an inflammatory form of cell death. When activated by inflammatory caspases, GSDMD is cleaved to form the N-terminal fragment (GSDMD-NT), which oligomerizes in membranes to form pores. These pores are visible under electron microscopy and bind to phosphatidylinositol phosphates, phosphatidylserine, and cardiolipin. Mutations in four conserved basic residues block GSDMD-NT oligomerization, membrane binding, pore formation, and pyroptosis. GSDMD-NT oligomerizes in the plasma membrane and kills cells from within, without harming neighboring cells. It also kills free bacteria in vitro and may have a direct bactericidal effect within host cells. The study confirms that GSDMD-NT forms pores that permeabilize mammalian membranes during pyroptosis, and that these pores are selective for lipids present on the inner leaflet of the plasma membrane. The findings suggest that GSDMD-NT's selective activity helps control tissue damage and limits the spread of infection.The study investigates the mechanism by which gasdermin D (GSDMD) triggers pyroptosis, an inflammatory form of cell death. When activated by inflammatory caspases, GSDMD is cleaved to form the N-terminal fragment (GSDMD-NT), which oligomerizes in membranes to form pores. These pores are visible under electron microscopy and bind to phosphatidylinositol phosphates, phosphatidylserine, and cardiolipin. Mutations in four conserved basic residues block GSDMD-NT oligomerization, membrane binding, pore formation, and pyroptosis. GSDMD-NT oligomerizes in the plasma membrane and kills cells from within, without harming neighboring cells. It also kills free bacteria in vitro and may have a direct bactericidal effect within host cells. The study confirms that GSDMD-NT forms pores that permeabilize mammalian membranes during pyroptosis, and that these pores are selective for lipids present on the inner leaflet of the plasma membrane. The findings suggest that GSDMD-NT's selective activity helps control tissue damage and limits the spread of infection.
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