Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.,EMBO Molecular Medicine

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Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-10-07 , DOI: 10.15252/emmm.201910547
Flora Magnotti ₁ , Lucie Lefeuvre _{1,

2} , Sarah Benezech _{1,

2} , Tiphaine Malsot ₁ , Louis Waeckel _{1,

2} , Amandine Martin ₁ , Sébastien Kerever ₃ , Daria Chirita ₁ , Marine Desjonqueres _{2,

4} , Agnès Duquesne _{2,

4} , Mathieu Gerfaud-Valentin _{2,

5} , Audrey Laurent _{2,

4} , Pascal Sève _{2,

5} , Michel-Robert Popoff ₆ , Thierry Walzer ₁ , Alexandre Belot _{1,

2,

4} , Yvan Jamilloux _{1,

2,

5} , Thomas Henry ₁

Affiliation

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.

中文翻译：

吡林去磷酸化足以触发家族性地中海热患者的炎性体活化。

家族性地中海热（FMF）是最常见的遗传性全身性自发性炎症综合征。FMF通常是由编码Pyrin的MEFV基因中的双等位基因突变引起的。确诊的遗传证据不足，约有30％被诊断为临床FMF的患者。Pyrin是一种炎症小体传感器，被两种激酶（PKN1 / 2）保持非活性。MEFV突变对炎症小体激活的后果仍然知之甚少。在这里，我们证明PKC超家族抑制剂在FMF患者的单核细胞中触发炎症小体激活，而在健康供体的单核细胞中触发延迟的细胞凋亡。致病性p.M694V MEFV等位基因的表达对于PKC抑制剂（或阻止Pyrin磷酸化的突变）触发caspase-1和gasdermin D介导的细胞凋亡是必要和充分的。与秋水仙碱对患者的疗效相一致，秋水仙碱可完全阻断FMF患者单核细胞的这种反应。这些结果表明，在FMF患者中，Pyrin炎性小体激活仅受Pyrin（去磷酸化）控制，而第二种控制机制在健康的供体/非FFM患者中限制了其激活。这项研究为MEFV变体的功能表征和诊断FMF的功能测试铺平了道路。

更新日期：2019-11-07

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