Publication Date:
2019
Description:
〈p〉Intracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptosis. The anthrax lethal factor metalloprotease and small-molecule DPP8/9 inhibitors both activate the NLRP1B inflammasome, but the molecular mechanism of NLRP1B activation is unknown. Here, we used genome-wide CRISPR/Cas9 knockout screens to identify genes required for NLRP1B-mediated pyroptosis. We discovered that lethal factor induces cell death via the N-end rule proteasomal degradation pathway. Lethal factor directly cleaves NLRP1B, inducing the N-end rule-mediated degradation of the NLRP1B N terminus and freeing the NLRP1B C terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the NLRP1B N terminus, but not via the N-end rule pathway. Thus, N-terminal degradation is the common activation mechanism of this innate immune sensor.〈/p〉
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Natural Sciences in General