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Pyroptosis in anti‐bacteria immunity: sensing and execution
Author(s) -
Shao Feng
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.403.3
Subject(s) - pyroptosis , caspase , microbiology and biotechnology , pyrin domain , inflammasome , cardiolipin , bacterial outer membrane , cytosol , autophagy , aim2 , chemistry , programmed cell death , biology , apoptosis , biochemistry , phospholipid , membrane , receptor , escherichia coli , enzyme , gene
Inflammatory caspases including caspase‐1, 4, 5 and 11 are critical for cytosolic defences against bacterial infections. Caspase‐1 is activated by canonical inflammasomes that sense diverse bacterial such as flagellin or pathogen virulence activity; caspase‐4/5 in human and caspase‐11 in mice are cytosolic receptors for bacterial LPS, determining Gram‐negative bacteria‐induced septic shock. Common to inflammatory caspases activation is pyroptosis, a programmed necrotic cell death. Using genome‐wide CRISPR/Cas9 screens, we identify GSDMD as a pyroptosis substrate for all inflammatory caspases. Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis. GSDMD contains a functionally important gasdermin‐N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. We show that the gasdermin‐N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane‐disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin‐N moved to the plasma membrane during pyroptosis. Purified gasdermin‐N efficiently lysed phosphoinositide/cardiolipin‐containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10~14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two‐domain architecture that is conserved in the gasdermin family. Structure‐guided mutagenesis demonstrated that the liposome‐leakage and pore‐forming activities of the gasdermin‐N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.