Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death

Cell Rep. 2020 Aug 11;32(6):108008. doi: 10.1016/j.celrep.2020.108008.


Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms.

Keywords: GBP1; Salmonella enterica Typhimurium; Toxoplasma gondii; apoptosis; caspases; inflammasomes; pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspases / immunology*
  • Cell Death / immunology
  • GTP-Binding Proteins / immunology*
  • HEK293 Cells
  • Humans
  • Inflammasomes / immunology
  • Interferon-gamma / pharmacology
  • Ligands
  • Salmonella Infections / immunology
  • Salmonella Infections / microbiology
  • Salmonella typhimurium / immunology*
  • THP-1 Cells
  • Toxoplasma / genetics
  • Toxoplasma / immunology*
  • Toxoplasmosis / immunology
  • Toxoplasmosis / microbiology
  • Vacuoles / immunology


  • GBP1 protein, human
  • Inflammasomes
  • Ligands
  • Interferon-gamma
  • Caspases
  • GTP-Binding Proteins