Journal
NATURE IMMUNOLOGY
Volume 21, Issue 8, Pages 880-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-020-0697-2
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Funding
- MRC [U105170648]
- Wellcome Trust [WT104752MA]
- NIH National Institutes of Allergy and Infectious Diseases [R01AI068041-13, R01AI108834-05]
- MRC [MR/T001917/1, MC_U105170648] Funding Source: UKRI
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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-gamma-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 byShigella flexneri, a cytosol-adapted bacterium, provide compelling evolutionary evidence for the importance of the GBP-caspase-4 pathway in antibacterial defense. How lipopolysaccharide embedded in bacterial membranes is sensed by intracellular defense mechanisms has been puzzling. Randow and colleagues show that guanylate-binding proteins assemble on the surface of Gram-negative bacteria to initiate downstream pyroptosis.
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