Activation of the CARD8 Inflammasome Requires a Disordered Region

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Cytosolic pattern-recognition receptors (PRRs) form inflammasomes, activating caspase-1 (CASP1) and inducing pyroptosis.
• DPP8/9 inhibitors activate human NLRP1 and CARD8 inflammasomes, which share similar C-terminal structures.
• CARD8 and NLRP1 inflammasomes have distinct N-termini but undergo autoproteolysis.

Purpose of the Study:

• To elucidate the mechanism by which DPP8/9 inhibitors activate the CARD8 inflammasome.
• To investigate the role of protein degradation pathways in inflammasome activation.
• To understand how CARD8 signals the activation of cellular degradation pathways.

Main Methods:

• Inhibition of dipeptidyl peptidases DPP8 and DPP9 (DPP8/9).
• Analysis of inflammasome complex formation and activation.
• Investigation of protein degradation pathways targeting CARD8.
• Assessment of caspase-1 (CASP1) activation and pyroptosis induction.

Main Results:

• DPP8/9 inhibition activates a proteasomal degradation pathway for misfolded proteins.
• The N-terminus of CARD8, containing a disordered region, is targeted for degradation.
• Degradation of the CARD8 N-terminus frees its C-terminal fragment, activating CASP1.
• This process leads to pyroptotic cell death.

Conclusions:

• CARD8 acts as a sensor for the activation of proteasomal degradation pathways.
• DPP8/9 inhibition triggers CARD8 inflammasome activation via targeted protein degradation.
• The findings reveal a novel mechanism linking protein quality control to innate immune responses and pyroptosis.