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

Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14384-14389. doi: 10.1073/pnas.1613156113. Epub 2016 Nov 22.


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.

Keywords: FMF; Pyrin; colchicine; inflammasome; microtubules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / toxicity
  • CARD Signaling Adaptor Proteins / metabolism
  • Clostridium Infections / immunology
  • Clostridium Infections / metabolism
  • Enterotoxins / toxicity
  • Familial Mediterranean Fever / genetics*
  • Familial Mediterranean Fever / immunology
  • Familial Mediterranean Fever / metabolism*
  • HEK293 Cells
  • Humans
  • Inflammasomes / drug effects
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubules / drug effects
  • Microtubules / immunology
  • Microtubules / metabolism
  • Mutation*
  • Pyrin / genetics*
  • Pyrin / immunology
  • Pyrin / metabolism*
  • Tubulin / metabolism


  • Bacterial Toxins
  • CARD Signaling Adaptor Proteins
  • Enterotoxins
  • Inflammasomes
  • Lipopolysaccharides
  • MEFV protein, human
  • Mefv protein, mouse
  • PYCARD protein, human
  • Pyrin
  • Tubulin
  • tcdA protein, Clostridium difficile