Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome

Nature. 2014 Sep 11;513(7517):237-41. doi: 10.1038/nature13449. Epub 2014 Jun 11.

Abstract

Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism
  • Burkholderia cenocepacia / metabolism
  • Caspase 1 / metabolism
  • Cell Line
  • Clostridium difficile / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Inflammasomes / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mutation
  • Protein Binding
  • Pyrin
  • Receptors, Pattern Recognition / metabolism
  • U937 Cells
  • rho GTP-Binding Proteins / metabolism*

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • Cytoskeletal Proteins
  • Inflammasomes
  • MEFV protein, human
  • Mefv protein, mouse
  • Pyrin
  • Receptors, Pattern Recognition
  • toxB protein, Clostridium difficile
  • Caspase 1
  • rho GTP-Binding Proteins