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.