دورية أكاديمية
أعرض في EDS

Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice.

التفاصيل البيبلوغرافية
العنوان: Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice.
المؤلفون: Dufies O; Université Côte d'Azur, Inserm, C3M, Nice, France., Doye A; Université Côte d'Azur, Inserm, C3M, Nice, France., Courjon J; Université Côte d'Azur, Inserm, C3M, Nice, France.; Université Côte d'Azur, CHU Nice, Nice, France., Torre C; Université Côte d'Azur, Inserm, C3M, Nice, France., Michel G; Université Côte d'Azur, Inserm, C3M, Nice, France., Loubatier C; Université Côte d'Azur, Inserm, C3M, Nice, France., Jacquel A; Université Côte d'Azur, Inserm, C3M, Nice, France., Chaintreuil P; Université Côte d'Azur, Inserm, C3M, Nice, France., Majoor A; Université Côte d'Azur, Inserm, C3M, Nice, France., Guinamard RR; Université Côte d'Azur, Inserm, C3M, Nice, France., Gallerand A; Université Côte d'Azur, Inserm, C3M, Nice, France., Saavedra PHV; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Verhoeyen E; Université Côte d'Azur, Inserm, C3M, Nice, France.; CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France., Rey A; CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France., Marchetti S; Université Côte d'Azur, Inserm, C3M, Nice, France., Ruimy R; Université Côte d'Azur, Inserm, C3M, Nice, France.; Université Côte d'Azur, CHU Nice, Nice, France., Czerucka D; Centre Scientifique de Monaco, Monaco, Monaco.; LIA ROPSE, Laboratoire International Associé Université Côte d'Azur, Centre Scientifique de Monaco, Nice, France., Lamkanfi M; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Py BF; CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France., Munro P; Université Côte d'Azur, Inserm, C3M, Nice, France., Visvikis O; Université Côte d'Azur, Inserm, C3M, Nice, France., Boyer L; Université Côte d'Azur, Inserm, C3M, Nice, France. laurent.boyer@univ-cotedazur.fr.; LIA ROPSE, Laboratoire International Associé Université Côte d'Azur, Centre Scientifique de Monaco, Nice, France. laurent.boyer@univ-cotedazur.fr.
المصدر: Nature microbiology [Nat Microbiol] 2021 Mar; Vol. 6 (3), pp. 401-412. Date of Electronic Publication: 2021 Jan 11.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101674869 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2058-5276 (Electronic) Linking ISSN: 20585276 NLM ISO Abbreviation: Nat Microbiol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Publishing Group, [2016]-
مواضيع طبية MeSH: Bacteremia/*metabolism , Bacterial Toxins/*metabolism , Escherichia coli/*metabolism , Escherichia coli Infections/*metabolism , Escherichia coli Proteins/*metabolism , Inflammasomes/*metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism , rac GTP-Binding Proteins/*metabolism, Animals ; Bacteremia/immunology ; Bacteremia/microbiology ; Bacterial Load ; Bacterial Toxins/genetics ; Escherichia coli/genetics ; Escherichia coli Infections/immunology ; Escherichia coli Infections/microbiology ; Escherichia coli Proteins/genetics ; Immunity, Innate ; Mice ; Phosphorylation ; Signal Transduction ; p21-Activated Kinases/metabolism ; rac GTP-Binding Proteins/genetics ; RAC2 GTP-Binding Protein
مستخلص: Inflammasomes are signalling platforms that are assembled in response to infection or sterile inflammation by cytosolic pattern recognition receptors. The consequent inflammasome-triggered caspase-1 activation is critical for the host defence against pathogens. During infection, NLRP3, which is a pattern recognition receptor that is also known as cryopyrin, triggers the assembly of the inflammasome-activating caspase-1 through the recruitment of ASC and Nek7. The activation of the NLRP3 inflammasome is tightly controlled both transcriptionally and post-translationally. Despite the importance of the NLRP3 inflammasome regulation in autoinflammatory and infectious diseases, little is known about the mechanism controlling the activation of NLRP3 and the upstream signalling that regulates the NLRP3 inflammasome assembly. We have previously shown that the Rho-GTPase-activating toxin from Escherichia coli cytotoxic necrotizing factor-1 (CNF1) activates caspase-1, but the upstream mechanism is unclear. Here, we provide evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activate host Rho GTPases. We demonstrate that this activation relies on the monitoring of the toxin's activity on the Rho GTPase Rac2. We also show that the NLRP3 inflammasome is activated by a signalling cascade that involves the p21-activated kinases 1 and 2 (Pak1/2) and the Pak1-mediated phosphorylation of Thr 659 of NLRP3, which is necessary for the NLRP3-Nek7 interaction, inflammasome activation and IL-1β cytokine maturation. Furthermore, inhibition of the Pak-NLRP3 axis decreases the bacterial clearance of CNF1-expressing UTI89 E. coli during bacteraemia in mice. Taken together, our results establish that Pak1 and Pak2 are critical regulators of the NLRP3 inflammasome and reveal the role of the Pak-NLRP3 signalling axis in vivo during bacteraemia in mice.
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معلومات مُعتمدة: 616986 International ERC_ European Research Council
المشرفين على المادة: 0 (Bacterial Toxins)
0 (Escherichia coli Proteins)
0 (Inflammasomes)
0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (Nlrp3 protein, mouse)
106803-33-2 (cytotoxic necrotizing factor type 1)
EC 2.7.11.1 (Pak1 protein, mouse)
EC 2.7.11.1 (Pak2 protein, mouse)
EC 2.7.11.1 (p21-Activated Kinases)
EC 3.6.5.2 (rac GTP-Binding Proteins)
تواريخ الأحداث: Date Created: 20210112 Date Completed: 20210512 Latest Revision: 20231213
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7116836
DOI: 10.1038/s41564-020-00832-5
PMID: 33432150
قاعدة البيانات: MEDLINE
الوصف
تدمد:2058-5276
DOI:10.1038/s41564-020-00832-5