Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients - CIRI - Activation et transduction du signal dans les lymphocytes Accéder directement au contenu
Article Dans Une Revue EMBO Molecular Medicine Année : 2019

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients

Résumé

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.
Fichier principal
Vignette du fichier
Pyrin_dephosphorylation_is_sufficient_to_trigger_inflammasome.pdf (2.35 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

hal-02407259 , version 1 (16-12-2019)

Licence

Paternité

Identifiants

Citer

Flora Magnotti, Lucie Lefeuvre, Sarah Benezech, Tiphaine Malsot, Louis Waeckel, et al.. Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. EMBO Molecular Medicine, 2019, 11 (11), pp.e10547. ⟨10.15252/emmm.201910547⟩. ⟨hal-02407259⟩
188 Consultations
84 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More