TY - JOUR
T1 - Functional degradation
T2 - A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes
AU - Sandstrom, Andrew
AU - Mitchell, Patrick S.
AU - Goers, Lisa
AU - Mu, Edward W.
AU - Lesser, Cammie F.
AU - Vance, Russell E.
N1 - Publisher Copyright:
© The Authors,
PY - 2019/4/5
Y1 - 2019/4/5
N2 - Inflammasomes are multiprotein 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. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-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.
AB - Inflammasomes are multiprotein 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. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-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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U2 - 10.1126/science.aau1330
DO - 10.1126/science.aau1330
M3 - Article
C2 - 30872533
AN - SCOPUS:85064284525
SN - 0036-8075
VL - 364
JO - Science
JF - Science
IS - 6435
M1 - eaau1330
ER -