title: Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation.
abstract: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Van Gorp
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Pedro H V
authors.initials: PH
authors.lastname: Saavedra
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Nathalia M
authors.initials: NM
authors.lastname: de Vasconcelos
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: Van Opdenbosch
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Vande Walle
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Matusiak
authors.affiliation: Rheumatology Unit, Bambino Gesù Children's Hospital, Rome, I-00146, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Prencipe
authors.affiliation: Rheumatology Unit, Bambino Gesù Children's Hospital, Rome, I-00146, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Insalaco
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Demon
authors.affiliation: Clinical Immunology Research Laboratory, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.|Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.|Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, B-9000, Belgium.
authors.forename: Delfien J
authors.initials: DJ
authors.lastname: Bogaert
authors.affiliation: Clinical Immunology Research Laboratory, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.|Laboratory of Immunoregulation, Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.
authors.forename: Melissa
authors.initials: M
authors.lastname: Dullaers
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Tino
authors.initials: T
authors.lastname: Hochepied
authors.affiliation: Department of Pediatric Rheumatology, Ghent University Hospital, Ghent, B-9000, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Dehoorne
authors.affiliation: Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.|Tumor Immunology Laboratory, Department of Pulmonary Medicine, Ghent University Hospital, Ghent, B-9000, Belgium.
authors.forename: Karim Y
authors.initials: KY
authors.lastname: Vermaelen
authors.affiliation: Clinical Immunology Research Laboratory, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.|Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.|Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, B-9000, Belgium.
authors.forename: Filomeen
authors.initials: F
authors.lastname: Haerynck
authors.affiliation: Rheumatology Unit, Bambino Gesù Children's Hospital, Rome, I-00146, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
authors.affiliation: Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium; mohamed.lamkanfi@irc.vib-ugent.be.|Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D003015:Clostridium Infections / Q000276:immunology / Q000378:metabolism; D004768:Enterotoxins / Q000633:toxicity; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D000071198:Pyrin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D053468:CARD Signaling Adaptor Proteins; D004768:Enterotoxins; D058847:Inflammasomes; D008070:Lipopolysaccharides; C000604192:MEFV protein, human; C000604193:Mefv protein, mouse; C402202:PYCARD protein, human; D000071198:Pyrin; D014404:Tubulin; C041348:tcdA protein, Clostridium difficile
keywords: FMF; Pyrin; colchicine; inflammasome; microtubules