NLRP3 Sensing of Diverse Inflammatory Stimuli Requires Distinct Structural Features
| Autor: | Abhinit Nagar, Tabassum Rahman, Jonathan A. Harton, Ellen B. Duffy, Kendi Okuda, Neal S. Silverman |
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| Rok vydání: | 2020 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
Repetitive Sequences Amino Acid 0301 basic medicine Inflammasomes Immunology caspase-1 Caspase 1 NLR Proteins Ligands Pyrin domain Mice 03 medical and health sciences 0302 clinical medicine NLRP3 inflammasome Leucine NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Immunology and Allergy leucine-rich repeats (LRRs) Francisella cysteine Original Research Adaptor Proteins Signal Transducing integumentary system Chemistry Mechanism (biology) Macrophages ROS Pyrin Domain Inflammasome Listeria monocytogenes Pyrin domain (PYD) Cell biology HEK293 Cells 030104 developmental biology IL-1β NLRP3 inflammasome activation lcsh:RC581-607 Apoptosis Regulatory Proteins Function (biology) 030215 immunology medicine.drug |
| Zdroj: | Frontiers in Immunology, Vol 11 (2020) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Popis: | The NLRP3 inflammasome is central to host defense and implicated in various inflammatory diseases and conditions. While the favored paradigm of NLRP3 inflammasome activation stipulates a unifying signal intermediate that de-represses NLRP3, this view has not been tested. Further, structures within NLRP3 required for inflammasome activation are poorly defined. Here we demonstrate that while the NLRP3 LRRs are not auto-repressive and are not required for inflammasome activation by all agonists, distinct sequences within the NLRP3 LRRs positively and negatively modulate inflammasome activation by specific ligands. In addition, elements within the HD1/HD2 “hinge” of NLRP3 and the nucleotide-binding domain have contrasting functions depending upon the specific agonists. Further, while NLRP3 1–432 is minimally sufficient for inflammasome activation by all agonists tested, the pyrin, and linker domains (1–134) function cooperatively and are sufficient for inflammasome activation by certain agonists. Conserved cysteines 8 and 108 appear important for inflammasome activation by sterile, but not infectious insults. Our results define common and agonist-specific regions of NLRP3 that likely mediate ligand-specific responses, discount the hypothesis that NLRP3 inflammasome activation has a unified mechanism, and implicate NLRP3 as an integrator of agonist-specific, inflammasome activating signals. |
| Databáze: | OpenAIRE |
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