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Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores

Liu, Xing ; Zhang, Zhibin ; Ruan, Jianbin ; Pan, Youdong ; Magupalli, Venkat Giri ; Wu, Hao ; Lieberman, Judy

Nature (London), 2016-07, Vol.535 (7610), p.153-158 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores
Autor: Liu, Xing ; Zhang, Zhibin ; Ruan, Jianbin ; Pan, Youdong ; Magupalli, Venkat Giri ; Wu, Hao ; Lieberman, Judy
Assuntos: Amino Acid Sequence ; Animals ; Apoptosis ; Bacteria ; Bacterial infections ; Cardiolipins - metabolism ; Cell Line ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; Cell Membrane - ultrastructure ; Cell Membrane Permeability - drug effects ; Cells ; Conserved Sequence - genetics ; Escherichia coli - cytology ; Escherichia coli - drug effects ; Escherichia coli - metabolism ; Humans ; Immunology ; Infections ; Inflammasomes - metabolism ; Liposomes - chemistry ; Liposomes - metabolism ; Listeria monocytogenes - cytology ; Listeria monocytogenes - drug effects ; Listeria monocytogenes - metabolism ; Membrane Proteins - chemistry ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Membranes ; Mice ; Mice, Inbred C57BL ; Microbial Viability - drug effects ; Microscopy, Electron ; Molecular Sequence Data ; Mutation ; Neoplasm Proteins - chemistry ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Neoplasm Proteins - pharmacology ; Observations ; Phosphatidylinositol Phosphates - metabolism ; Phosphatidylserines - metabolism ; Plasmids ; Porosity - drug effects ; Protein Multimerization - genetics ; Protein Structure, Tertiary - genetics ; Protein Transport ; Proteins ; Pyroptosis - drug effects ; Pyroptosis - genetics ; Staphylococcus aureus - cytology ; Staphylococcus aureus - drug effects ; Staphylococcus aureus - metabolism
É parte de: Nature (London), 2016-07, Vol.535 (7610), p.153-158
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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These authors contributed equally to this work.
Descrição: Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores

Liu, Xing ; Zhang, Zhibin ; Ruan, Jianbin ; Pan, Youdong ; Magupalli, Venkat Giri ; Wu, Hao ; Lieberman, Judy

England: Nature Publishing Group

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