期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 8, 期 332, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaf1471
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资金
- ERC Start Grant IMMUNO
- Interuniversity Attraction Poles (T-TIME)
- Research Fund KU Leuven
- FWO (Research Foundation-Flanders) fellowship
- Australian Research Council Future Fellowship [FT130100361]
- INSERM
- GIS (Groupement d'Interet Scientifique)-Institut des Maladies Rares
- Victorian State Government Operational Infrastructure Scheme Grant [1057815, 1016647]
- Independent Research Institute Infrastructure Support Scheme Grant [361646]
- Australian National Health and Medical Research Council
Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1 beta (IL-1 beta). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familialMediterranean 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-1b production. Successful therapy targeting IL-1b has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-likemechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.
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