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Caspase-1 interdomain linker cleavage is required for pyroptosis

Daniel P Ball1, Cornelius Y Taabazuing1, Andrew R Griswold2

  • 1Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Life Science Alliance
|February 14, 2020
PubMed

Insights

Pathogen recognition receptors (PRRs) form inflammasomes to trigger cell death. This study reveals that pro-caspase-1 self-cleavage is essential for pyroptosis, regardless of inflammasome structure.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Pattern-recognition receptors (PRRs) initiate inflammatory responses by forming inflammasomes.
  • Canonical inflammasomes typically recruit the ASC adapter protein to activate pro-caspase-1 and induce pyroptosis.
  • ASC-independent inflammasomes, which bypass ASC, have been proposed but their mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of pro-caspase-1 autoproteolysis in ASC-dependent and ASC-independent inflammasomes.
  • To characterize the inflammasome formation and signaling mechanisms of human PRRs NLRP1 and CARD8.
  • To identify the first canonical inflammasome-forming PRR that operates independently of ASC.

Main Methods:

  • Utilized human PRRs NLRP1 and CARD8 to form ASC-dependent and ASC-independent inflammasomes, respectively.
  • Investigated pro-caspase-1 activation and autoproteolysis in both inflammasome types.
  • Assessed the requirement of pro-caspase-1 autoproteolysis for pyroptosis induction.

Main Results:

  • NLRP1 exclusively forms ASC-dependent inflammasomes, while CARD8 forms ASC-independent inflammasomes.
  • CARD8 is identified as the first canonical inflammasome-forming PRR that does not utilize ASC.
  • Both NLRP1 (ASC-dependent) and CARD8 (ASC-independent) inflammasomes require pro-caspase-1 autoproteolysis for pyroptosis.

Conclusions:

  • Pro-caspase-1 autoproteolysis is a critical regulatory step for pyroptosis induced by human canonical inflammasomes.
  • Inflammasome structure (ASC-dependent vs. ASC-independent) does not alter the requirement for pro-caspase-1 self-cleavage.
  • This finding provides new insights into the conserved mechanisms of inflammasome activation and pyroptosis.

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