Academic Journal
Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients
| العنوان: | Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients |
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| المؤلفون: | Magnotti, Flora, Lefeuvre, Lucie, Benezech, Sarah, Malsot, Tiphaine, Waeckel, Louis, Martin, Amandine, Kerever, Sebastien, Chirita, Daria, Desjonqueres, Marine, Duquesne, Agnès, Gerfaud-Valentin, Mathieu, Laurent, Audrey, Sève, Pascal, Popoff, Michel-Robert, Walzer, Thierry, Belot, Alexandre, Jamilloux, Yvan, Henry, Thomas |
| المساهمون: | Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation CIRI (I2BA), Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Université Paris Diderot - Paris 7 (UPD7)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie, rhumatologie et dermatologie pédiatriques Hôpital Femme Mère Enfant, HCL, Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, Département de Médecine Interne Hôpital de la Croix-Rousse, HCL, Hôpital de la Croix-Rousse CHU - HCL, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Médecine Interne Hôpital Croix Rousse, CHU Lyon, CHU Lyon-Hôpital de la Croix-Rousse CHU - HCL, Toxines bactériennes - Bacterial Toxins, Institut Pasteur Paris (IP), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases CIRI, This work is supported by an ANR grant (FMFgeneToDiag #ANR‐17‐CE17‐0021), an ERC‐2012‐StG_3115 and funding from the European Union's Horizon 2020 research and innovation program under grant agreement #779295 (ImmunAID)., This work was performed in the framework of the Centre National de Reférence RAISE. We acknowledge the contribution of the Etablissement Français du Sang Auvergne—Rhône‐Alpes and of SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) Cytometry, Microscopy, and Vectorology facilities., ANR-17-CE17-0021,FMFgeneToDiag,Fièvre Méditerranéenne Familiale (FMF) et maladies apparentées : des bases moléculaires et cellulaires à la mise au point de tests diagnostiques(2017) |
| المصدر: | ISSN: 1757-4676. |
| بيانات النشر: | HAL CCSD Wiley Open Access |
| سنة النشر: | 2019 |
| المجموعة: | Université Jean Monnet – Saint-Etienne: HAL |
| مصطلحات موضوعية: | caspase-1, autoinflammation, colchicine, diagnosis, pyroptosis, [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology |
| الوصف: | International audience ; 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/31589380; PUBMED: 31589380; PUBMEDCENTRAL: PMC6835204 |
| DOI: | 10.15252/emmm.201910547 |
| الاتاحة: | https://hal.science/hal-02407259 https://hal.science/hal-02407259v1/document https://hal.science/hal-02407259v1/file/Pyrin_dephosphorylation_is_sufficient_to_trigger_inflammasome.pdf https://doi.org/10.15252/emmm.201910547 |
| Rights: | http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.CDFF7A62 |
| قاعدة البيانات: | BASE |
| DOI: | 10.15252/emmm.201910547 |
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