Caspase-11 Activation Requires Lysis of Pathogen-Containing Vacuoles by IFN-induced GTPases

Nature. 2014 May 15;509(7500):366-70. doi: 10.1038/nature13157. Epub 2014 Apr 16.

Abstract

Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / immunology
  • Caspases / metabolism*
  • Cytosol / microbiology
  • Enzyme Activation
  • GTP Phosphohydrolases / metabolism*
  • Galectins / immunology
  • Gram-Negative Bacteria / growth & development
  • Gram-Negative Bacteria / immunology*
  • Gram-Negative Bacteria / pathogenicity
  • Immunity, Innate / immunology
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Interferon Type I / immunology*
  • Lipopolysaccharides / immunology
  • Mice
  • Phagosomes / immunology
  • Phagosomes / microbiology
  • Salmonella typhimurium / growth & development
  • Salmonella typhimurium / immunology
  • Vacuoles / microbiology*

Substances

  • Galectins
  • Inflammasomes
  • Interferon Type I
  • Lipopolysaccharides
  • galectin-8, mouse
  • Casp4 protein, mouse
  • Caspases
  • GTP Phosphohydrolases