Science https://doi.org/10.1126/science.aau1330 & https://doi.org/10.1126/science.aau1208 (2019)

Pathogens such as Bacillus anthracis and Shigella flexneri encode factors that trigger activation of NLRP1 inflammasomes. In Science, Sandstrom et al. and Chui et al. reveal that NLRP1 is an intracellular decoy protein whose N-terminal domain requires proteasomal degradation for inflammasome activation. Mouse NLRP1 and human CARD8 have a C-terminal caspase-recruitment domain (CARD) preceded by a ‘function-to-find’ domain that undergoes constitutive autoprocessing to yield non-covalently linked NLRP1 fragments. B. anthracis lethal toxin directly cleaves the N-terminal portion of NLRP1, whereas the S. flexneri–encoded E3 ubiquitin ligase IpaH7.8 modifies NLRP1. Both processes lead to proteasome-mediated degradation of the N-terminal NLRP1 domain, which releases the C-terminal CARD to activate caspase-1 and trigger cellular pyroptosis. Chui et al. provide genetic evidence of host-encoded E3 ligases of the N-end rule proteasomal degradation pathway in lethal toxin–initiated activation of NLRP1. Thus, proteasomal targeting of NLRP1 leads to its functional activation.