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

Je-Wook Yu1, Teresa Fernandes-Alnemri, Pinaki Datta

  • 1Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Molecular Cell
|October 30, 2007
PubMed

Insights

Mutations in PSTPIP1 cause PAPA syndrome by overactivating pyrin. This protein complex assembly leads to inflammasome activation, explaining the autoinflammatory condition.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • PAPA syndrome is an autoinflammatory disease linked to mutations in PSTPIP1.
  • The precise molecular mechanisms underlying PSTPIP1-mediated autoinflammation remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which PSTPIP1 mutations lead to PAPA syndrome.
  • To investigate the interaction between PSTPIP1 and pyrin in inflammasome activation.

Main Methods:

  • Biochemical assays to study protein-protein interactions.
  • Analysis of pyrin oligomerization and activation.
  • Characterization of PSTPIP1 mutants in pyrin activation.

Main Results:

  • PSTPIP1 is required for the assembly of the ASC pyroptosome, which activates caspase-1.
  • Pyrin acts as a cytosolic receptor for PSTPIP1, existing in an autoinhibited state.
  • PSTPIP1 binding unmasks pyrin's PYD, facilitating ASC interaction and pyroptosome formation.
  • PAPA-associated PSTPIP1 mutants exhibit enhanced pyrin binding and activation.

Conclusions:

  • Constitutive activation of pyrin by mutant PSTPIP1 proteins drives the autoinflammatory phenotype in PAPA syndrome.
  • The PSTPIP1-pyrin interaction is a critical step in inflammasome activation and PAPA pathogenesis.

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