scholarly journals The N‐end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin

2019 ◽  
Vol 38 (13) ◽  
Author(s):  
Hao Xu ◽  
Jianjin Shi ◽  
Hang Gao ◽  
Ying Liu ◽  
Zhenxiao Yang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Lethal Toxin ◽  
Inflammasome Activation ◽  
Anthrax Lethal Toxin

scholarly journals Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

2018 ◽  
Author(s):  
Andrew Sandstrom ◽  
Patrick S. Mitchell ◽  
Lisa Goers ◽  
Edward W. Mu ◽  
Cammie F. Lesser ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Ubiquitin Ligase ◽  
Shigella Flexneri ◽  
Lethal Toxin ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Anthrax Lethal Toxin ◽  
Degradation Model ◽  
Caspase 1 ◽  
Necessary And Sufficient

AbstractInflammasomes 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, aShigella flexneriubiquitin 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 SummaryTwo distinct pathogen enzymes activate an innate immune sensor called NLRP1B by a mechanism that requires proteasome-mediated degradation of NLRP1B.

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

Science ◽  
2019 ◽  
Vol 364 (6435) ◽  
pp. eaau1330 ◽  
Author(s):  
Andrew Sandstrom ◽  
Patrick S. Mitchell ◽  
Lisa Goers ◽  
Edward W. Mu ◽  
Cammie F. Lesser ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Ubiquitin Ligase ◽  
Shigella Flexneri ◽  
Inflammasome Activation ◽  
Anthrax Lethal Toxin ◽  
Degradation Model ◽  
Amino Terminal ◽  
Caspase 1 ◽  
Carboxyl Terminal ◽  
Necessary And Sufficient

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, aShigella flexneriubiquitin 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.

scholarly journals Auranofin Protects against Anthrax Lethal Toxin-Induced Activation of the Nlrp1b Inflammasome

2010 ◽  
Vol 55 (3) ◽  
pp. 1028-1035 ◽  
Author(s):  
Zachary L. Newman ◽  
Nicole Sirianni ◽  
Christina Mawhinney ◽  
Margaret S. Lee ◽  
Stephen H. Leppla ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Lethal Factor ◽  
Molecular Probes ◽  
Lethal Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Inflammasome Activation ◽  
Anthrax Lethal Toxin ◽  
Caspase 1 ◽  
Mouse Macrophages ◽  
Inhibitory Drug

ABSTRACTAnthrax lethal toxin (LT) is the major virulence factor forBacillus anthracis. The lethal factor (LF) component of this bipartite toxin is a protease which, when transported into the cellular cytoplasm, cleaves mitogen-activated protein kinase kinase (MEK) family proteins and induces rapid toxicity in mouse macrophages through activation of the Nlrp1b inflammasome. A high-throughput screen was performed to identify synergistic LT-inhibitory drug combinations from within a library of approved drugs and molecular probes. From this screen we discovered that auranofin, an organogold compound with anti-inflammatory activity, strongly inhibited LT-mediated toxicity in mouse macrophages. Auranofin did not inhibit toxin transport into cells or MEK cleavage but inhibited both LT-mediated caspase-1 activation and caspase-1 catalytic activity. Thus, auranofin inhibited LT-mediated toxicity by preventing activation of the Nlrp1b inflammasome and the downstream actions that occur in response to the toxin. Idebenone, an analog of coenzyme Q, synergized with auranofin to increase its protective effect. We found that idebenone functions as an inhibitor of voltage-gated potassium channels and thus likely mediates synergy through inhibition of the potassium fluxes which have been shown to be required for Nlrp1b inflammasome activation.

Cytotoxic effects of anthrax lethal toxin on macrophage-like cell line J774A.1

1996 ◽  
Vol 33 (4) ◽  
pp. 224-227 ◽  
Author(s):  
Ching-Gong Lin ◽  
Yi-Tien Kao ◽  
Wen-Tssann Liu ◽  
Hsin-Hsien Huang ◽  
Kuo-Ching Chen ◽  
...  
Keyword(s):  
Cell Line ◽  
Lethal Toxin ◽  
Anthrax Lethal Toxin ◽  
Cytotoxic Effects

scholarly journals Inactivation of Rho GTPases by Statins Attenuates Anthrax Lethal Toxin Activity

2008 ◽  
Vol 77 (1) ◽  
pp. 348-359 ◽  
Author(s):  
Aimee M. deCathelineau ◽  
Gary M. Bokoch
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Protective Antigen ◽  
Biological Effects ◽  
Lethal Factor ◽  
Lethal Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Gtpase Activity ◽  
Anthrax Lethal Toxin ◽  
Reductase Inhibitors

ABSTRACT Anthrax lethal factor (LF), secreted by Bacillus anthracis, interacts with protective antigen to form a bipartite toxin (lethal toxin [LT]) that exerts pleiotropic biological effects resulting in subversion of the innate immune response. Although the mitogen-activated protein kinase kinases (MKKs) are the major intracellular protein targets of LF, the pathology induced by LT is not well understood. The statin family of HMG-coenzyme A reductase inhibitors have potent anti-inflammatory effects independent of their cholesterol-lowering properties, which have been attributed to modulation of Rho family GTPase activity. The Rho GTPases regulate vesicular trafficking, cytoskeletal dynamics, and cell survival and proliferation. We hypothesized that disruption of Rho GTPase function by statins might alter LT action. We show here that statins delay LT-induced death and MKK cleavage in RAW macrophages and that statin-mediated effects on LT action are attributable to disruption of Rho GTPases. The Rho GTPase-inactivating toxin, toxin B, did not significantly affect LT binding or internalization, suggesting that the Rho GTPases regulate trafficking and/or localization of LT once internalized. The use of drugs capable of inhibiting Rho GTPase activity, such as statins, may provide a means to attenuate intoxication during B. anthracis infection.

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