Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 29, Pages 18124-18133Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.645549
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Funding
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development
- National Institutes of Health R01 [HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01HL114453, HL116472]
- Department of Veterans Affairs
- Flight Attendant Medical Research Institute
- American Heart Association [12SDG12040330]
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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-1 beta and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1 beta in cells. Here we show that LPS increases the NALP3 protein life-span 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-1 beta 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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