Journal
SCIENCE
Volume 364, Issue 6435, Pages 82-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aau1208
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Funding
- Josie Robertson Foundation
- Stand Up to Cancer-Innovative Research Grant [SU2C-AACR-IRG11-17]
- Stand Up to Cancer is a program of the Entertainment Industry Foundation
- Pew Charitable Trusts
- NIH [R01 AI137168, T32 GM007739, T32 GM115327, P30 CA008748]
- Alfred P. Sloan Foundation Research Fellowship
- American Cancer Society [PF-17-224-01 - CCG]
- Gabrielle's Angel Foundation
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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. In this study, 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.
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