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The PYRIN-CARD protein ASC is an activating adaptor for caspase-1

Srinivasa M Srinivasula1, Jean-Luc Poyet, Marjaneh Razmara

  • 1Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

The Journal of Biological Chemistry
|April 23, 2002
PubMed

Insights

The PYRIN-CARD protein ASC acts as an adaptor, linking procaspase-1 to initiate inflammatory signaling. ASC

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • The PYRIN and CARD domains are part of the six-helix bundle death domain-fold superfamily.
  • These domains mediate the assembly of signaling complexes in apoptotic and inflammatory pathways.

Purpose of the Study:

  • To elucidate the function of the PYRIN-CARD protein ASC in caspase-1 activation.
  • To investigate the role of ASC's domains in assembling signaling complexes.

Main Methods:

  • Investigated ASC's interaction with procaspase-1 using CARD-CARD interactions.
  • Ectopic expression of ASC and its domains with procaspase-1 in transfected cells.
  • Utilized an inducible FKBP12 oligomerization domain to substitute ASC's PYRIN domain.
  • Assessed interleukin-1beta generation in THP-1 cells expressing ASC's CARD domain.

Main Results:

  • ASC specifically interacts with procaspase-1, inducing its oligomerization and activation.
  • Full-length ASC, but not isolated domains, activated procaspase-1 and processed pro-interleukin-1beta.
  • The PYRIN domain acts as an oligomerization domain, while the CARD domain acts as an effector domain.
  • Expression of ASC's CARD domain reduced interleukin-1beta generation.

Conclusions:

  • ASC is a crucial adaptor protein in the caspase-1 signaling pathway.
  • ASC mediates the assembly of a caspase-1-inflammasome complex upon pro-inflammatory cytokine stimulation.

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