Research Article

Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

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Science  14 Mar 2019:
eaau1330
DOI: 10.1126/science.aau1330

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Abstract

Inflammasomes are multi-protein platforms that initiate innate immunity by recruitment and activation of Caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. Here we find that cleavage results in proteasome-mediated degradation of the N-terminal domains of NLRP1B, liberating a C-terminal fragment that is a potent Caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our “functional degradation” model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

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