Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants

Mol Cell. 2007 Oct 26;28(2):214-27. doi: 10.1016/j.molcel.2007.08.029.


The molecular mechanism by which mutations in the cytoskeleton-organizing protein PSTPIP1 cause the autoinflammatory PAPA syndrome is still elusive. Here, we demonstrate that PSTPIP1 requires the familial Mediterranean fever protein pyrin to assemble the ASC pyroptosome, a molecular platform that recruits and activates caspase-1. We provide evidence that pyrin is a cytosolic receptor for PSTPIP1. Pyrin exists as a homotrimer in an autoinhibited state due to intramolecular interactions between its pyrin domain (PYD) and B-box. Ligation by PSTPIP1, which is also a homotrimer, activates pyrin by unmasking its PYD, thereby allowing it to interact with ASC and facilitate ASC oligomerization into an active ASC pyroptosome. Because of their high binding affinity to pyrin's B-box, PAPA-associated PSTPIP1 mutants were found to be more effective than WT PSTPIP1 in inducing pyrin activation. Therefore, constitutive ligation and activation of pyrin by mutant PSTPIP1 proteins explain the autoinflammatory phenotype seen in PAPA syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / metabolism*
  • Cell Line
  • Colchicine / pharmacology
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Familial Mediterranean Fever / genetics
  • Familial Mediterranean Fever / immunology
  • Familial Mediterranean Fever / metabolism*
  • Genetic Vectors
  • Genotype
  • Humans
  • Immunity, Innate
  • Interleukin-1beta / metabolism
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Multiprotein Complexes / metabolism
  • Mutation*
  • Nocodazole / pharmacology
  • Phenotype
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Pyrin
  • Recombinant Fusion Proteins / metabolism
  • Retroviridae / genetics
  • Transfection
  • Tubulin Modulators / pharmacology


  • Adaptor Proteins, Signal Transducing
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • Interleukin-1beta
  • MEFV protein, human
  • Multiprotein Complexes
  • PSTPIP1 protein, human
  • PYCARD protein, human
  • Pyrin
  • Recombinant Fusion Proteins
  • Tubulin Modulators
  • Caspase 1
  • Nocodazole
  • Colchicine