Caspase-1 interdomain linker cleavage is required for pyroptosis

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.