title: 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.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2].
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [3].
authors.forename: Jieling
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Gao
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Gong
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Jianzhong Jeff
authors.initials: JJ
authors.lastname: Xi
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Fengchao
authors.initials: F
authors.lastname: Wang
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [3] National Institute of Biological Sciences, Beijing, Collaborative Innovation Center for Cancer Medicine, Beijing 102206, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shao
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D057508:Burkholderia cenocepacia / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D016360:Clostridioides difficile / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D011485:Protein Binding; D000071198:Pyrin; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D020298:U937 Cells; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C000604192:MEFV protein, human; C000604193:Mefv protein, mouse; D000071198:Pyrin; D051192:Receptors, Pattern Recognition; C031815:toxB protein, Clostridium difficile; D020170:Caspase 1; D020741:rho GTP-Binding Proteins