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

[familial mediterranean fever]

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 C 3 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 (T 6 SS ). 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 .

Diseases
Validation

Diseases presenting "fever" symptom

22q11.2 deletion syndrome

acute rheumatic fever

alexander disease

allergic bronchopulmonary aspergillosis

canavan disease

carcinoma of the gallbladder

child syndrome

congenital toxoplasmosis

cushing syndrome

cystinuria

dracunculiasis

erdheim-chester disease

esophageal adenocarcinoma

esophageal carcinoma

familial mediterranean fever

focal myositis

hodgkin lymphoma, classical

lamellar ichthyosis

legionellosis

locked-in syndrome

malignant atrophic papulosis

neonatal adrenoleukodystrophy

neuralgic amyotrophy

oculocutaneous albinism

papillon-lefèvre syndrome

pyomyositis

pyruvate dehydrogenase deficiency

scrub typhus

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

typhoid

waldenström macroglobulinemia

wolf-hirschhorn syndrome

This symptom has already been validated