Authors: S. L. Masters, V. Lagou, I. Jeru, P. J. Baker, L. Van Eyck, D. A. Parry, D. Lawless, D. De Nardo, J. E. Garcia-Perez, L. F. Dagley, C. L. Holley, J. Dooley, F. Moghaddas, E. Pasciuto, P.-Y. Jeandel, R. Sciot, D. Lyras, A. I. Webb, S. E. Nicholson, L. De Somer, E. van Nieuwenhove, J. Ruuth-Praz, B. Copin, E. Cochet, M. Medlej-Hashim, A. Megarbane, K. Schroder, S. Savic, A. Goris, S. Amselem, C. Wouters, A. Liston
Summary:
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.
Source:
Science Translational Medicine; 2016, 8 (332): 332ra45