Mammals express a number of pattern-recognition receptors (PRRs) to detect intracellular pathogens and danger signals in the cytosol of host cells. Several of these PRRs, once activated, assemble into multiprotein complexes called canonical inflammasomes. These canonical inflammasomes activate caspase-1 (CASP1), which cleaves and activates inflammatory cytokines and gasdermin D, inducing a lytic form of programmed cell death called pyroptosis. NLRP1 and CARD8 are related PRRs that can form canonical inflammasomes, but their activation mechanisms have remained largely uncharacterized. Interestingly, both NLRP1 and CARD8 have C-terminal regions that undergo post-translational autoproteolysis to generate two non-covalently associated fragments. The anthrax lethal factor (LF) metalloprotease is the most studied NLRP1 activator, but it only activates a subset of rodent NLRP1 alleles and not human NLRP1 or CARD8. We discovered that LF induces cell death via the N-end rule proteasomal degradation pathway in the mouse NLRP1B allele. LF directly cleaves NLRP1B, which renders it more susceptible for targeted degradation via the N-end rule. The break in the polypeptide chain from autoproteolysis enables the NLRP1B C-terminus to avoid degradation and is instead freed to activate CASP1 and cause pyroptosis. Our lab also discovered that inhibitors of the dipeptidyl peptidases 8 and 9 (DPP8/9), like Val-boroPro (VbP), activate both the NLRP1 and CARD8 inflammasomes, but this mechanism, unlike LF, does not involve direct cleavage. NLRP1 and CARD8 share a common C- terminal region, but they have entirely different N-terminal regions. NLRP1 contains a number of well-folded domains, but CARD8 only contains a putative unstructured region of ~160 amino acids. We discovered that DPP8/9 inhibition activates a proteasomal degradation pathway that targets CARD8 and other disordered and misfolded proteins for destruction. Thus, in humans, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins. This work has revealed that N-terminal degradation is the common activation mechanism between the NLRP1 and CARD8 inflammasomes.