Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms

Nat Immunol. 2020 Aug;21(8):880-891. doi: 10.1038/s41590-020-0697-2. Epub 2020 Jun 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases, Initiator / immunology*
  • GTP-Binding Proteins / immunology*
  • Gram-Negative Bacteria / immunology
  • Gram-Negative Bacterial Infections / immunology*
  • HeLa Cells
  • Humans
  • Inflammasomes / immunology*
  • Lipopolysaccharides / immunology
  • Mice
  • Pyroptosis / immunology
  • Signal Transduction / immunology*


  • Inflammasomes
  • Lipopolysaccharides
  • Caspases, Initiator
  • GTP-Binding Proteins