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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)14384-14389
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
Publication statusPublished - Dec 13 2016

Keywords

  • Journal Article

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    Van Gorp, H., Saavedra, P. H. V., de Vasconcelos, N. M., Van Opdenbosch, N., Vande Walle, L., Matusiak, M., Prencipe, G., Insalaco, A., Van Hauwermeiren, F., Demon, D., Bogaert, D. J., Dullaers, M., De Baere, E., Hochepied, T., Dehoorne, J., Vermaelen, K. Y., Haerynck, F., De Benedetti, F., & Lamkanfi, M. (2016). Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation. Proceedings of the National Academy of Sciences of the United States of America, 113(50), 14384-14389. https://doi.org/10.1073/pnas.1613156113