Abstract:
:Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inactive by two kinases (PKN1/2). The consequences of MEFV mutations on inflammasome activation are still poorly understood. Here, we demonstrate that PKC superfamily inhibitors trigger inflammasome activation in monocytes from FMF patients while they trigger a delayed apoptosis in monocytes from healthy donors. The expression of the pathogenic p.M694V MEFV allele is necessary and sufficient for PKC inhibitors (or mutations precluding Pyrin phosphorylation) to trigger caspase-1- and gasdermin D-mediated pyroptosis. In line with colchicine efficacy in patients, colchicine fully blocks this response in FMF patients' monocytes. These results indicate that Pyrin inflammasome activation is solely controlled by Pyrin (de)phosphorylation in FMF patients while a second control mechanism restricts its activation in healthy donors/non-FMF patients. This study paves the way toward a functional characterization of MEFV variants and a functional test to diagnose FMF.
journal_name
EMBO Mol Medjournal_title
EMBO molecular medicineauthors
Magnotti F,Lefeuvre L,Benezech S,Malsot T,Waeckel L,Martin A,Kerever S,Chirita D,Desjonqueres M,Duquesne A,Gerfaud-Valentin M,Laurent A,Sève P,Popoff MR,Walzer T,Belot A,Jamilloux Y,Henry Tdoi
10.15252/emmm.201910547subject
Has Abstractpub_date
2019-11-07 00:00:00pages
e10547issue
11eissn
1757-4676issn
1757-4684journal_volume
11pub_type
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