TY - JOUR
T1 - Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase
AU - Han, SeungHye
AU - Lear, Travis B.
AU - Jerome, Jacob A.
AU - Rajbhandari, Shristi
AU - Snavely, Courtney A.
AU - Gulick, Dexter L.
AU - Gibson, Kevin F.
AU - Zou, Chunbin
AU - Chen, Bill B.
AU - Mallampalli, Rama K.
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/7/17
Y1 - 2015/7/17
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M115.645549
DO - 10.1074/jbc.M115.645549
M3 - Article
C2 - 26037928
AN - SCOPUS:84937468257
SN - 0021-9258
VL - 290
SP - 18124
EP - 18133
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -