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

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.

• Authors: Hao Xu, Jieling Yang, Wenqing Gao, Lin Li, Peng Li, Li Zhang, Yi-Nan Gong, Xiaolan Peng, Jianzhong Jeff Xi, She Chen, Fengchao Wang, Feng Shao
• Journal: Nature (Nature) Vol. 513 Issue 7517 Pg. 237-41 (Sep 11 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 24919149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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