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

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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-1 beta 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.
Keywords
FMF, Pyrin, inflammasome, colchicine, microtubules, HIGH GENE-FREQUENCY, AUTOINFLAMMATORY DISEASES, NLRP3 INFLAMMASOME, CLOSTRIDIUM-DIFFICILE, EXPRESSION, COLCHICINE, REGISTRY, IMMUNE, RECOGNITION, MACROPHAGES

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Citation

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Chicago
Van Gorp, Hanne, Pedro Henrique Viana Saavedra, Nathalia Moraes de Vasconcelos, Nina Van Opdenbosch, Lieselotte Vande Walle, Magdalena Matusiak, Giusi Prencipe, et al. 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.
APA
Van Gorp, H., Viana Saavedra, P. H., Moraes de Vasconcelos, N., Van Opdenbosch, N., Vande Walle, L., Matusiak, M., Prencipe, G., et al. (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.
Vancouver
1.
Van Gorp H, Viana Saavedra PH, Moraes de Vasconcelos N, Van Opdenbosch N, Vande Walle L, Matusiak M, et al. 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. 2016;113(50):14384–9.
MLA
Van Gorp, Hanne, Pedro Henrique Viana Saavedra, Nathalia Moraes de Vasconcelos, et al. “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 (2016): 14384–14389. Print.
@article{8507472,
  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-1 beta 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.},
  author       = {Van Gorp, Hanne and Viana Saavedra, Pedro Henrique and Moraes de Vasconcelos, Nathalia and Van Opdenbosch, Nina and Vande Walle, Lieselotte and Matusiak, Magdalena and Prencipe, Giusi and Insalaco, Antonella and Van Hauwermeiren, Filip and Demon, Dieter and Bogaert, Delfien and Dullaers, Melissa and De Baere, Elfride and Hochepied, Tino and Dehoorne, Jo and Vermaelen, Karim and HAERYNCK, FILOMEEN and De Benedetti, Fabrizio and Lamkanfi, Mohamed},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  keyword      = {FMF,Pyrin,inflammasome,colchicine,microtubules,HIGH GENE-FREQUENCY,AUTOINFLAMMATORY DISEASES,NLRP3 INFLAMMASOME,CLOSTRIDIUM-DIFFICILE,EXPRESSION,COLCHICINE,REGISTRY,IMMUNE,RECOGNITION,MACROPHAGES},
  language     = {eng},
  number       = {50},
  pages        = {14384--14389},
  title        = {Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation},
  url          = {http://dx.doi.org/10.1073/pnas.1613156113},
  volume       = {113},
  year         = {2016},
}

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