Open AccessGuanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms
Author(s) -
Michal P. Wandel,
Bae-Hoon Kim,
EuiSoon Park,
Keith B. Boyle,
Komal Nayak,
Brice Lagrange,
Adrian Herod,
Thomas Henry,
Matthias Zilbauer,
John R. Rohde,
John D. MacMicking,
Felix Randow
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0697-2
Subject(s) - pyroptosis , microbiology and biotechnology , cytosol , shigella flexneri , caspase , biology , inflammasome , signal transduction , intracellular parasite , caspase 1 , intracellular , programmed cell death , apoptosis , biochemistry , inflammation , immunology , escherichia coli , enzyme , gene
Bacterial lipopolysaccharide triggers human caspase-4 (murine caspase-11) to cleave gasdermin-D and induce pyroptotic cell death. How lipopolysaccharide sequestered in the membranes of cytosol-invading bacteria activates caspases remains unknown. Here we show that in interferon-γ-stimulated cells guanylate-binding proteins (GBPs) assemble on the surface of Gram-negative bacteria into polyvalent signaling platforms required for activation of caspase-4. Caspase-4 activation is hierarchically controlled by GBPs; GBP1 initiates platform assembly, GBP2 and GBP4 control caspase-4 recruitment, and GBP3 governs caspase-4 activation. In response to cytosol-invading bacteria, activation of caspase-4 through the GBP platform is essential to induce gasdermin-D-dependent pyroptosis and processing of interleukin-18, thereby destroying the replicative niche for intracellular bacteria and alerting neighboring cells, respectively. Caspase-11 and GBPs epistatically protect mice against lethal bacterial challenge. Multiple antagonists of the pathway encoded by Shigella flexneri, a cytosol-adapted bacterium, provide compelling evolutionary evidence for the importance of the GBP-caspase-4 pathway in antibacterial defense.