Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cell Death and Disease Année : 2023

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

Michel Popoff

Résumé

Abstract Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. In addition, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.
Fichier principal
Vignette du fichier
Dasha-CHSB302.2-Cddis-2023.pdf (3.65 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte
Licence

Dates et versions

hal-04607569 , version 1 (10-06-2024)

Licence

Identifiants

Citer

Daria Chirita, Pauline Bronnec, Flora Magnotti, Sarah Dalmon, Amandine Martin, et al.. Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation. Cell Death and Disease, 2023, 14 (3), pp.213. ⟨10.1038/s41419-023-05745-9⟩. ⟨hal-04607569⟩
0 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More