Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
Details
Publication Year 2016-03-30, Volume 8, Issue #332, Page 332ra45
Journal Title
Sci Transl Med
Publication Type
Journal Article
Abstract
Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1beta (IL-1beta). 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 inMEFV, 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 asClostridiumdifficiletoxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1beta production. Successful therapy targeting IL-1beta 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.
Publisher
AAAS
WEHI Research Division(s)
Inflammation; Systems Biology And Personalised Medicine
PubMed ID
27030597
Rights Notice
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Creation Date: 2016-04-05 01:44:05
Last Modified: 2016-04-05 03:09:26
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