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Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase.
Han, SeungHye; Lear, Travis B; Jerome, Jacob A; Rajbhandari, Shristi; Snavely, Courtney A; Gulick, Dexter L; Gibson, Kevin F; Zou, Chunbin; Chen, Bill B; Mallampalli, Rama K.
Afiliación
  • Han S; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Lear TB; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Jerome JA; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Rajbhandari S; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Snavely CA; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Gulick DL; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Gibson KF; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Zou C; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Chen BB; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
  • Mallampalli RK; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Department of Cell Biology, Physiology, and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Medical Specialty Service Line, Veterans Affairs Pittsburgh
J Biol Chem ; 290(29): 18124-18133, 2015 Jul 17.
Article en En | MEDLINE | ID: mdl-26037928
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-1ß and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1ß 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-1ß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Portadoras / Lipopolisacáridos / Ubiquitina-Proteína Ligasas / Proteínas F-Box / Inflamasomas Límite: Humans Idioma: En Revista: J Biol Chem Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Portadoras / Lipopolisacáridos / Ubiquitina-Proteína Ligasas / Proteínas F-Box / Inflamasomas Límite: Humans Idioma: En Revista: J Biol Chem Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos