Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. Issue 11 (7th October 2019)

• Record Type: Journal Article
• Authors: Magnotti, Flora; Lefeuvre, Lucie; Benezech, Sarah; Malsot, Tiphaine; Waeckel, Louis; Martin, Amandine; Kerever, Sébastien; Chirita, Daria; Desjonqueres, Marine; Duquesne, Agnès; Gerfaud‐Valentin, Mathieu; Laurent, Audrey; Sève, Pascal; Popoff, Michel‐Robert; Walzer, Thierry; Belot, Alexandre; Jamilloux, Yvan; Henry, Thomas
• Is Part Of: EMBO molecular medicine. Volume 11:Issue 11(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-10-07
• Subjects: autoinflammation -- caspase‐1 -- colchicine -- diagnosis -- pyroptosis; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201910547
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Familial Mediterranean fever (FMF) is a systemic auto‐inflammatory disease associated with MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor. The link between MEFV mutations and the dysregulated activation of the Pyrin inflammasome observed in FMF patients is unclear. Pyrin dephosphorylation is insufficient to trigger full inflammasome activation in healthy donors'monocytes while it is sufficient in FMF patients monocytes. The pathogenic MEFV mutation most frequently observed in FMF patients triggers constitutive inflammasome activation only when combined to a phosphonull MEFV mutation. UCN‐01‐induced dephosphorylation of Pyrin triggers inflammasome activation in FMF patients' monocytes but not in monocytes from other patients paving the way to a functional diagnosis of FMF. Abstract : Familial Mediterranean fever (FMF) is a systemic auto‐inflammatory disease associated with MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor. The link between MEFV mutations and the dysregulated activation of the Pyrin inflammasome observed in FMF patients is unclear.