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 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 Mycotoxin Zearalenone Attenuates Innate Immune Responses and Suppresses NLRP3 Inflammasome Activation in LPS-Activated Macrophages

Toxins ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 593
Author(s):  
Po-Yen Lee ◽  
Ching-Chih Liu ◽  
Shu-Chi Wang ◽  
Kai-Yin Chen ◽  
Tzu-Chieh Lin ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Adverse Effects ◽  
Signaling Pathways ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Mammalian Species ◽  
Inflammasome Activation ◽  
Amino Terminal ◽  
Proinflammatory Mediators ◽  
Nlrp3 Inflammasome Activation

Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E2 (PGE2)), decreased the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), inhibited the activation of c-Jun amino-terminal kinase (JNK), p38 and nuclear factor-κB (NF-κB) signaling pathways, and repressed the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. These results indicated that mycotoxin ZEA attenuates macrophage-mediated innate immunity upon LPS stimulation, suggesting that the intake of mycotoxin ZEA-contaminated food might result in decreasing innate immunity, which has a higher risk of adverse effects during infection.

scholarly journals Identification of Epitope and Surface-Exposed Domains of Shigella flexneri Invasion Plasmid Antigen D (IpaD)

1998 ◽  
Vol 66 (5) ◽  
pp. 1999-2006 ◽  
Author(s):  
K. Ross Turbyfill ◽  
Jennifer A. Mertz ◽  
Corey P. Mallett ◽  
Edwin V. Oaks
Keyword(s):  
Amino Acid ◽  
Shigella Flexneri ◽  
Serum Antibody ◽  
Terminal Region ◽  
Virulence Plasmid ◽  
Amino Acid Residues ◽  
Unique Region ◽  
Amino Terminal ◽  
Convalescent Phase ◽  
Carboxyl Terminal

ABSTRACT Transport and surface expression of the invasion plasmid antigens (Ipa proteins) is an essential trait in the pathogenicity ofShigella spp. In addition to the type III protein secretion system encoded by the mxi/spa loci on the large virulence plasmid, transport of IpaB and IpaC into the surrounding medium is modulated by IpaD. To characterize the structural topography of IpaD, the Geysen epitope-mapping system was used to identify epitopes recognized by surface-reactive monoclonal and polyclonal antibodies produced against purified recombinant IpaD or synthetic IpaD peptides. Surface-exposed epitopes of IpaD were confined to the first 180 amino acid residues, whereas epitopes in the carboxyl-terminal half were not exposed on the Shigella surface. By using convalescent-phase sera from 10 Shigella flexneri-infected monkeys, numerous epitopes were mapped within a surface-exposed region of IpaD between amino acid residues 14 and 77. Epitopes were also identified in the carboxyl-terminal half of IpaD with a few convalescent-phase sera. Comparison of IpaD epitope sequences withSalmonella SipD sequences indicated that very similar epitopes may exist in the carboxyl-terminal region of each protein whereas the IpaD epitopes in the surface-exposed amino-terminal region were unique for the Shigella protein. Although the IpaD and SipD homologs may play similar roles in transport, the dominant serum antibody response to IpaD is against the unique region of this protein exposed on the surface of the pathogen.

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 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.

scholarly journals Activation of the Nlrp1b Inflammasome by Reduction of Cytosolic ATP

2012 ◽  
Vol 81 (2) ◽  
pp. 570-579 ◽  
Author(s):  
Kuo-Chieh Liao ◽  
Jeremy Mogridge
Keyword(s):  
Pattern Recognition ◽  
Dominant Negative ◽  
Atp Depletion ◽  
Metabolic Inhibitors ◽  
Binding Motif ◽  
Inflammasome Activation ◽  
Anthrax Lethal Toxin ◽  
Caspase 1 ◽  
Anthrax Infection ◽  
Inflammasome Activity

ABSTRACTThe efficacy of the innate immune system depends on its ability to mount an appropriate response to diverse infections and damaging agents. Key components of this system are pattern recognition receptors that detect pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs). Nlrp1b is a pattern recognition receptor that forms a caspase-1 activation platform, known as an inflammasome, upon sensing the proteolytic activity of anthrax lethal toxin. The activation of caspase-1 leads to the release of proinflammatory cytokines that aid in the clearance of the anthrax infection. Here, we demonstrate that Nlrp1b also becomes activated in cells that are subjected to energy stress caused by metabolic inhibitors or by nutrient deprivation. Glucose starvation and hypoxia were used to correlate the level of cytosolic ATP to the degree of inflammasome activation. Because lowering the ratio of cytosolic ATP to AMP activates the main cellular energy sensor, AMP-activated protein kinase (AMPK), we assessed whether AMPK promoted inflammasome activity by using a combination of small interfering RNA (siRNA) and transfection of a dominant negative AMPK subunit. We found that AMPK promoted inflammasome activity, but activation of AMPK in the absence of ATP depletion was not sufficient for caspase-1-mediated pro-interleukin 1β (pro-IL-1β) processing. Finally, we found that mutation of the ATP-binding motif of Nlrp1b caused constitutive activation, suggesting that ATP might inhibit the Nlrp1b inflammasome instead of being required for its assembly.

scholarly journals Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

2019 ◽  
Vol 17 (12) ◽  
pp. 1245-1256 ◽  
Author(s):  
Yuting Jin ◽  
Changyong Li ◽  
Dongwei Xu ◽  
Jianjun Zhu ◽  
Song Wei ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Inflammatory Injury ◽  
Notch1 Signaling ◽  
Caspase 1 ◽  
Hepatocellular Damage ◽  
Hepatocellular Apoptosis

AbstractNotch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

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