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Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase
- Source :
- Journal of Biological Chemistry. 290:18124-18133
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- The inflammasome is a multiprotein complex that augments the proinflammatory response by increasing the generation and cellular release of key cytokines. Specifically, the NALP3 inflammasome requires two-step signaling, priming and activation, to be functional to release the proinflammatory cytokines IL-1β and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1β in cells. Here we show that LPS increases the NALP3 protein lifespan without significantly altering steady-state mRNA in human cells. LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. A unique small molecule inhibitor of FBXO3 restores FBXL2 levels, resulting in decreased NALP3 protein levels in cells and, thereby, reducing the release of IL-1β and IL-18 in human inflammatory cells after NALP3 activation. Our findings uncover NALP3 as a molecular target for FBXL2 and suggest that therapeutic targeting of the inflammasome may serve as a platform for preclinical intervention.
- Subjects :
- Lipopolysaccharides
Inflammasomes
Ubiquitin-Protein Ligases
Immunology
Interleukin-1beta
NALP3
Biochemistry
F-box protein
Cell Line
Proinflammatory cytokine
AIM2
Ubiquitin
NLR Family, Pyrin Domain-Containing 3 Protein
medicine
Humans
Molecular Biology
SKP Cullin F-Box Protein Ligases
biology
F-Box Proteins
Interleukin-18
Ubiquitination
Inflammasome
Cell Biology
Immunity, Innate
Ubiquitin ligase
Cell biology
Proteolysis
biology.protein
lipids (amino acids, peptides, and proteins)
Interleukin 18
Carrier Proteins
medicine.drug
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 290
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....889b7658d9884224cc4e6dce52ba50d2