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Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14384-14389. Epub 2016 Nov 22.

Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation.

Author information

1
Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.
2
Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium.
3
Rheumatology Unit, Bambino Gesù Children's Hospital, Rome, I-00146, Italy.
4
Clinical Immunology Research Laboratory, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.
5
Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, B-9000, Belgium.
6
Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, B-9000, Belgium.
7
Laboratory of Immunoregulation, Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium.
8
Center for Medical Genetics Ghent, Ghent University, Ghent, B-9000, Belgium.
9
Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9000, Belgium.
10
Department of Pediatric Rheumatology, Ghent University Hospital, Ghent, B-9000, Belgium.
11
Tumor Immunology Laboratory, Department of Pulmonary Medicine, Ghent University Hospital, Ghent, B-9000, Belgium.
12
Inflammation Research Center, VIB, Zwijnaarde, B-9052, Belgium; mohamed.lamkanfi@irc.vib-ugent.be.

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.

KEYWORDS:

FMF; Pyrin; colchicine; inflammasome; microtubules

PMID:
27911804
PMCID:
PMC5167202
DOI:
10.1073/pnas.1613156113
[Indexed for MEDLINE]
Free PMC Article

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