Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase

SeungHye Han, Travis B. Lear, Jacob A. Jerome, Shristi Rajbhandari, Courtney A. Snavely, Dexter L. Gulick, Kevin F. Gibson, Chunbin Zou, Bill B. Chen, Rama K. Mallampalli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


The inflammasome is a multiprotein complex that augments the proinflammatory response by increasing the generation and cellular release of key cytokines. Specifically, theNALP3inflammasome requires two-step signaling, priming and activation, to be functional to release the proinflammatory cytokines IL-1βand 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.

Original languageEnglish (US)
Pages (from-to)18124-18133
Number of pages10
JournalJournal of Biological Chemistry
Issue number29
StatePublished - Jul 17 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SC<sup>FFBXL2</sup> E3 ligase'. Together they form a unique fingerprint.

Cite this