scholarly journals N-terminal degradation activates the NLRP1B inflammasome

Science ◽  
2019 ◽  
Vol 364 (6435) ◽  
pp. 82-85 ◽  
Author(s):  
Ashley J. Chui ◽  
Marian C. Okondo ◽  
Sahana D. Rao ◽  
Kuo Gai ◽  
Andrew R. Griswold ◽  
...  
Keyword(s):  
Lethal Factor ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Activation Mechanism ◽  
C Terminus ◽  
Anthrax Lethal Factor ◽  
Genome Wide ◽  
N Terminus ◽  
The Common ◽  
Inflammatory Caspases

Intracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptosis. The anthrax lethal factor metalloprotease and small-molecule DPP8/9 inhibitors both activate the NLRP1B inflammasome, but the molecular mechanism of NLRP1B activation is unknown. In this study, we used genome-wide CRISPR-Cas9 knockout screens to identify genes required for NLRP1B-mediated pyroptosis. We discovered that lethal factor induces cell death via the N-end rule proteasomal degradation pathway. Lethal factor directly cleaves NLRP1B, inducing the N-end rule–mediated degradation of the NLRP1B N terminus and freeing the NLRP1B C terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the NLRP1B N terminus but not via the N-end rule pathway. Thus, N-terminal degradation is the common activation mechanism of this innate immune sensor.

scholarly journals N-terminal degradation activates the Nlrp1b inflammasome

2018 ◽  
Author(s):  
Ashley J. Chui ◽  
Marian C. Okondo ◽  
Sahana D. Rao ◽  
Kuo Gai ◽  
Andrew R. Griswold ◽  
...  
Keyword(s):  
Cell Death ◽  
Lethal Factor ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Common Mechanism ◽  
Caspase 1 ◽  
C Terminus ◽  
Anthrax Lethal Factor ◽  
N Terminus ◽  
Inflammatory Caspases

AbstractIntracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptotic cell death. The anthrax lethal factor metalloprotease and small molecule DPP8/9 inhibitors both activate the Nlrp1b inflammasome, but the molecular mechanism of Nlrp1b activation is not known. Here, we used genome-wide CRISPR/Cas9 knockout screens to identify genes required for Nlrp1b-mediated pyroptosis, and discovered that lethal factor induces cell deathviathe N-end rule proteasomal degradation pathway. Lethal factor directly cleaves Nlrp1b, which induces the N-end rule-mediated degradation of the Nlrp1b N-terminus and thereby frees the Nlrp1b C-terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the Nlrp1b N-terminus, but, in contrast, not through the N-end rule pathway. Overall, these data reveal that N-terminal degradation is the common mechanism for activation of this innate immune sensor protein.One Sentence SummaryProteasome-mediated degradation of the Nlrp1b N-terminus releases the Nlrp1b C-terminus to activate caspase-1 and induce pyroptotic cell death.

Anthrax Lethal Factor Cleaves the N-Terminus of MAPKKs and Induces Tyrosine/Threonine Phosphorylation of MAPKs in Cultured Macrophages

1998 ◽  
Vol 248 (3) ◽  
pp. 706-711 ◽  
Author(s):  
Gaetano Vitale ◽  
Rossella Pellizzari ◽  
Chiara Recchi ◽  
Giorgio Napolitani ◽  
Michèle Mock ◽  
...  
Keyword(s):  
Lethal Factor ◽  
Anthrax Lethal Factor ◽  
N Terminus

scholarly journals Structural analysis of the OC43 coronavirus 2′-O-RNA methyltransferase

2021 ◽  
Author(s):  
Pavel Dostalik ◽  
Petra Krafcikova ◽  
Jan Silhan ◽  
Evzen Boura
Keyword(s):  
Structural Analysis ◽  
Rna Stability ◽  
Binding Pocket ◽  
Human Pathogen ◽  
C Terminus ◽  
N Terminus ◽  
High Conservation ◽  
The Common ◽  
Human Coronaviruses ◽  
Very High

The OC43 coronavirus is a human pathogen that usually causes only the common cold. One of its key enzymes, similar to other coronaviruses, is the 2′-O-RNA methyltransferase (MTase) that is essential for viral RNA stability and expression. Here, we report the crystal structure of the 2′-O-RNA MTase in a complex with the pan-methyltransferase inhibitor sinefungin solved at 2.2 Å resolution. The structure revealed an overall fold consistent with the fold observed in other coronaviral MTases. The major differences are in the conformation of the C-terminus of the nsp16 subunit and an additional helix in the N-terminus of the nsp10 subunits. The structural analysis also revealed very high conservation of the SAM binding pocket suggesting that the SAM pocket is a suitable spot for the design of antivirals effective against all human coronaviruses.

scholarly journals The N-end rule E3 ligase UBR2 activates Nlrp1b inflammasomes

2018 ◽  
Author(s):  
Hao Xu ◽  
Jianjin Shi ◽  
Zhenxiao Yang ◽  
Feng Shao ◽  
Na Dong
Keyword(s):  
Innate Immunity ◽  
Mouse Genome ◽  
Lethal Factor ◽  
E3 Ligase ◽  
Innate Immune ◽  
Anthrax Lethal Factor ◽  
Genome Wide ◽  
Bacterial Protease ◽  
Mouse Macrophages

AbstractInnate immunity relies on the formation of different inflammasomes to initiate immune responses. The recognition of diverse infection and other danger signals by innate immune receptors trigger caspase-1 activation that induces pyroptosis. Anthrax lethal factor (LF) is a secreted bacterial protease that known to potently activate Nlrp1b inflammasomes in mouse macrophages, but the molecular mechanism underlying LF-induced Nlrp1b activation remains unknown. We here carried out both a mouse genome-wide siRNA screen and a CRISPR/Cas9 knockout screen seeking to identify genes that participate in Nlrp1b activation triggered by LF treatment. We found that the N-end rule pathway E3 ligase UBR2 is required for Nlrp1b activation and a ubiquitin conjugating E2 enzyme E2O is also involved in this process via its physically interaction with UBR2. We show that LF triggers activation of Nlrp1b by initiating the degradation of the N-terminal fragment of Nlrp1b itself that produced via an auto-cleavage process. This study deepens our understanding of innate immunity defense against bacterial infection by elucidating the functional role of UBR2-mediated N-end rule pathway in LF-induced Nlrp1b activation.

Anthrax lethal factor cleaves the N-terminus of MAPKKS and induces tyrosine/threonine phosphorylation of MAPKS in cultured macrophages

1999 ◽  
Vol 87 (2) ◽  
pp. 288-288 ◽  
Author(s):  
G. Vitale ◽  
R. Pellizzari ◽  
C. Recchi ◽  
G. Napolitani ◽  
M. Mock ◽  
...  
Keyword(s):  
Lethal Factor ◽  
Anthrax Lethal Factor ◽  
N Terminus

Ligand binding and activation of the CGRP receptor

2007 ◽  
Vol 35 (4) ◽  
pp. 729-732 ◽  
Author(s):  
A.C. Conner ◽  
J. Simms ◽  
J. Barwell ◽  
M. Wheatley ◽  
D.R. Poyner
Keyword(s):  
G Protein ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Extracellular Loop ◽  
C Terminus ◽  
Calcitonin Gene ◽  
The Family ◽  
N Terminus ◽  
G Protein Coupled

The receptor for CGRP (calcitonin gene-related peptide) is a heterodimer between a GPCR (G-protein-coupled receptor), CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activity-modifying protein 1). Models have been produced of RAMP1 and CLR. It is likely that the C-terminus of CGRP interacts with the extracellular N-termini of CLR and RAMP1; the extreme N-terminus of CLR is particularly important and may interact directly with CGRP and also with RAMP1. The N-terminus of CGRP interacts with the TM (transmembrane) portion of the receptor; the second ECL (extracellular loop) is especially important. Receptor activation is likely to involve the relative movements of TMs 3 and 6 to create a G-protein-binding pocket, as in Family A GPCRs. Pro321 in TM6 appears to act as a pivot. At the base of TMs 2 and 3, Arg151, His155 and Glu211 may form a loose equivalent of the Family A DRY (Asp-Arg-Tyr) motif. Although the details of this proposed activation mechanism clearly do not apply to all Family B GPCRs, the broad outlines may be conserved.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

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