Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 3, Pages 582-597Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00775-14
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Funding
- National Institutes of Health (NIH) [AI083387]
- NIH/NIDCR [DE14318]
- CTSA [8UL1 TR000149]
- UTHSCSA
- NIH (CTRC MS Shared Resource) [7P30CA54174-14]
- NIH-NCI (San Antonio Cancer Institute) [P30 CA54174]
- NIH-NIA (Nathan Shock Center) [P30 AG013319]
- NIH-NIA [P01AG19316]
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Caspase-1 is activated by the inflammasome complex to process cytokines like interleukin-1 beta (IL-1 beta). Pro-caspase-1 consists of three domains, CARD, p20, and p10. Association of pro-caspase-1 with the inflammasome results in initiation of its autocatalytic activity, culminating in self-cleavage that generates catalytically active subunits (p10 and p20). In the current study, we show that Nedd8 is required for efficient self-cleavage of pro-caspase-1 to generate its catalytically active subunits. Nedd8 silencing or treating cells with the neddylation inhibitor MLN4924 led to diminished caspase-1 processing and reduced IL-1 beta maturation following inflammasome activation. Coimmunoprecipitation and mass spectrometric analysis of 293 cells overexpressing procaspase-1 (and CARD) and Nedd8 suggested possible neddylation of caspase-1 CARD. Following inflammasome activation in primary macrophages, we observed colocalization of endogenous Nedd8 with caspase-1. Similarly, interaction of endogenous Nedd8 with caspase-1 CARD was detected in inflammasome-activated macrophages. Furthermore, enhanced autocatalytic activity of pro-caspase-1 was observed following Nedd8 overexpression in 293 cells, and such activity in inflammasome-activated macrophages was drastically diminished upon treatment of cells with MLN4924. Thus, our studies demonstrate a role of Nedd8 in regulating caspase-1 activation following inflammasome activation, presumably via augmenting autoprocessing/cleavage of pro-caspase-1 into its corresponding catalytically active subunits.
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