Abstract:
: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.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Wandel MP,Kim BH,Park ES,Boyle KB,Nayak K,Lagrange B,Herod A,Henry T,Zilbauer M,Rohde J,MacMicking JD,Randow Fdoi
10.1038/s41590-020-0697-2subject
Has Abstractpub_date
2020-08-01 00:00:00pages
880-891issue
8eissn
1529-2908issn
1529-2916pii
10.1038/s41590-020-0697-2journal_volume
21pub_type
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