Familial auto inflammation with neutrophilic dermatosis reveals a novel regulatory mechanism of pyrin activation

Masters, Seth L., Lagou, Vasiliki, Jéru, Isabelle, Baker, Paul J., Van Eyck, Lien, Parry, David A., Lawless, Dylan, De Nardo, Dominic, Garcia-Perez, Josselyn E., Dagley, Laura F., Holley, Caroline L., Dooley, James, Moghaddas, Fiona, Pasciuto, Emanuela, Jeandel, Pierre-Yves, Sciot, Raf, Lyras, Dena, Webb, Andrew I., Nicholson, Sandra E., De Somer, Lien, van Nieuwenhove, Erika, Ruuth-Praz, Julia, Copin, Bruno, Cochet, Emmanuelle, Medlej-Hashim, Myrna, Megarbane, Andre, Schroder, Kate, Savic, Sinisa, Goris, An, Amselem, Serge, Wouters, Carine and Liston, Adrian (2016) Familial auto inflammation with neutrophilic dermatosis reveals a novel regulatory mechanism of pyrin activation. Science Translational Medicine, 8 332: 1-9. doi:10.1126/scitranslmed.aaf1471

Author Masters, Seth L.
Lagou, Vasiliki
Jéru, Isabelle
Baker, Paul J.
Van Eyck, Lien
Parry, David A.
Lawless, Dylan
De Nardo, Dominic
Garcia-Perez, Josselyn E.
Dagley, Laura F.
Holley, Caroline L.
Dooley, James
Moghaddas, Fiona
Pasciuto, Emanuela
Jeandel, Pierre-Yves
Sciot, Raf
Lyras, Dena
Webb, Andrew I.
Nicholson, Sandra E.
De Somer, Lien
van Nieuwenhove, Erika
Ruuth-Praz, Julia
Copin, Bruno
Cochet, Emmanuelle
Medlej-Hashim, Myrna
Megarbane, Andre
Schroder, Kate
Savic, Sinisa
Goris, An
Amselem, Serge
Wouters, Carine
Liston, Adrian
Title Familial auto inflammation with neutrophilic dermatosis reveals a novel regulatory mechanism of pyrin activation
Journal name Science Translational Medicine   Check publisher's open access policy
ISSN 1946-6234
Publication date 2016-03-30
Sub-type Article (original research)
DOI 10.1126/scitranslmed.aaf1471
Open Access Status Not Open Access
Volume 8
Issue 332
Start page 1
End page 9
Total pages 9
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Collection year 2017
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article number 332RA45

Document type: Journal Article
Sub-type: Article (original research)
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Institute for Molecular Bioscience - Publications
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Created: Fri, 01 Apr 2016, 16:10:08 EST by Dr Kate Schroder on behalf of School of Chemistry & Molecular Biosciences