Functional Degradation: A Mechanism of NLRP1 Inflammasome Activation by Diverse Pathogen Enzymes

Overview

Journal Science

Specialty Science

Date 2019 Mar 16

PMID 30872533

Citations 189

Authors

Andrew Sandstrom

Patrick S Mitchell

Lisa Goers

Edward W Mu

Cammie F Lesser

Russell E Vance

Affiliations

Soon will be listed here.

Abstract

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 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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