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Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

2016; National Academy of Sciences; Volume: 113; Issue: 50 Linguagem: Inglês

10.1073/pnas.1613156113

1091-6490

Hanne Van Gorp, Pedro Saavedra, Nathalia M. de Vasconcelos, Nina Van Opdenbosch, Lieselotte Vande Walle, Magdalena Matusiak, Giusi Prencipe, Antonella Insalaco, Filip Van Hauwermeiren, Dieter Demon, Debby Bogaert, Mélissa Dullaers, Elfride De Baere, Tino Hochepied, Joke Dehoorne, Karim Vermaelen, Filomeen Haerynck, Fabrizio De Benedetti, Mohamed Lamkanfi,

Cancer-related molecular mechanisms research

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.