Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes
| Autor: | Lisa Goers, Russell E. Vance, Edward W. Mu, Patrick S. Mitchell, Andrew Sandstrom, Cammie F. Lesser |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Inflammasomes medicine.medical_treatment Interleukin-1beta Inbred C57BL Shigella flexneri Mice 0302 clinical medicine Innate Multidisciplinary biology Chemistry Effector Caspase 1 Bacterial Adaptor Proteins Inflammasome Neoplasm Proteins Ubiquitin ligase Cell biology Infectious Diseases Host-Pathogen Interactions medicine.drug Proteasome Endopeptidase Complex Death Domain Receptor Signaling Adaptor Proteins General Science & Technology Ubiquitin-Protein Ligases Bacterial Toxins NLR Proteins Cleavage (embryo) Article Vaccine Related 03 medical and health sciences Enzyme activator Bacterial Proteins Protein Domains Biodefense medicine Animals Humans Antigens Innate immune system Protease Activator (genetics) Prevention Signal Transducing Immunity biology.organism_classification Enzyme Activation CARD Signaling Adaptor Proteins Protein Subunits HEK293 Cells RAW 264.7 Cells Emerging Infectious Diseases 030104 developmental biology Bacillus anthracis Proteolysis biology.protein Apoptosis Regulatory Proteins 030217 neurology & neurosurgery Peptide Hydrolases |
| Zdroj: | Science (New York, N.Y.), vol 364, iss 6435 |
| Popis: | 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, 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. |
| Databáze: | OpenAIRE |
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