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Journal Articles (Data Paper) Science Translational Medicine Year : 2016

Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

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Seth Masters
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  • PersonId : 1198235
James Dooley
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Dena Lyras
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Adrian Liston
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  • PersonId : 944648

Abstract

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.

Dates and versions

inserm-03884409 , version 1 (05-12-2022)

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Cite

Seth Masters, James Dooley, Vasiliki Lagou, Isabelle Jéru, Paul Baker, et al.. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Science Translational Medicine, 2016, 8 (332), pp.332ra45. ⟨10.1126/scitranslmed.aaf1471⟩. ⟨inserm-03884409⟩
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