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Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1

Christian Stehlik1, Sug Hyung Lee, Andrea Dorfleutner

  • 1Burnham Institute, La Jolla, CA 92037, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|November 25, 2003
PubMed

Insights

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) adapter protein regulates IL-1beta secretion by binding procaspase-1. ASC

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a unique bipartite adapter protein containing both CARD and PYRIN domains.
  • ASC plays a role in regulating caspase family proteases, particularly caspase-1, which is involved in inflammatory responses.

Purpose of the Study:

  • To investigate the role of ASC in regulating procaspase-1 activation and subsequent IL-1beta secretion.
  • To elucidate the mechanisms by which ASC interacts with other proteins and signaling pathways involved in inflammation.

Main Methods:

  • THP-1 monocytes and HEK293 cells were used to study ASC function.
  • Procaspase-1 activation was measured using protease activity assays.
  • IL-1beta secretion was quantified in cell culture supernatants.
  • Expression levels of ASC mRNA and protein were analyzed following stimulation with LPS and TNF.

Main Results:

  • ASC binds to procaspase-1 and adapter proteins, regulating IL-1beta activation in THP-1 monocytes.
  • ASC exhibits dual concentration-dependent effects on IL-1beta secretion, enhancing at low and suppressing at high concentrations.
  • In HEK293 cells, ASC interferes with Cardiak/Rip2/Rick-mediated procaspase-1 activation and forms cytosolic specks that sequester procaspase-1.
  • Coexpression of ASC with pyrin or cryopyrin enhances IL-1beta secretion, while ASC alone interferes with LPS/TNF-induced caspase-1 activation, indicating pathway competition.
  • LPS and TNF induce ASC expression in myeloid cells, suggesting cross-talk between cytokine signaling and the ASC pathway.

Conclusions:

  • ASC acts as a complex regulator of procaspase-1 activation and IL-1beta production, with its function modulated by concentration and interaction with other PAAD/PYRIN family proteins.
  • ASC plays a critical role in the interplay between inflammatory stimuli (LPS, TNF) and caspase-1-mediated cytokine signaling.
  • These findings highlight a novel regulatory mechanism for inflammatory responses involving the ASC adapter protein.

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