RT Journal Article
SR Electronic
T1 Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 317834
DO 10.1101/317834
A1 Andrew Sandstrom
A1 Patrick S. Mitchell
A1 Lisa Goers
A1 Edward W. Mu
A1 Cammie F. Lesser
A1 Russell E. Vance
YR 2018
UL http://biorxiv.org/content/early/2018/11/06/317834.abstract
AB 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 new ‘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.One Sentence Summary Two distinct pathogen enzymes activate an innate immune sensor called NLRP1B by a mechanism that requires proteasome-mediated degradation of NLRP1B.