Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria

Nat Commun. 2020 Jun 24;11(1):3276. doi: 10.1038/s41467-020-16889-z.


The human non-canonical inflammasome controls caspase-4 activation and gasdermin-D-dependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds and oligomerizes caspase-4, the pathway is thought to proceed without dedicated LPS sensors or an activation platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for non-canonical inflammasome activation by cytosolic Salmonella or upon cytosolic delivery of LPS. GBP1 associates with the surface of cytosolic Salmonella seconds after bacterial escape from their vacuole, initiating the recruitment of GBP2-4 to assemble a GBP coat. The GBP coat then promotes the recruitment of caspase-4 to the bacterial surface and caspase activation, in absence of bacteriolysis. Mechanistically, GBP1 binds LPS with high affinity through electrostatic interactions. Our findings indicate that in human epithelial cells GBP1 acts as a cytosolic LPS sensor and assembles a platform for caspase-4 recruitment and activation at LPS-containing membranes as the first step of non-canonical inflammasome signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspases, Initiator / metabolism*
  • Cell Line
  • Cytosol / microbiology*
  • Enzyme Activation
  • Epithelial Cells / metabolism
  • GTP-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Inflammasomes / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipopolysaccharides / metabolism*
  • Phosphate-Binding Proteins / metabolism
  • Protein Binding
  • Pyroptosis
  • Salmonella / metabolism*
  • Static Electricity


  • GBP1 protein, human
  • GSDMD protein, human
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Phosphate-Binding Proteins
  • CASP4 protein, human
  • Caspases, Initiator
  • GTP-Binding Proteins